Use of combined oral contraceptives containing nomegestrol acetate and estradiol

ABSTRACT

The present invention relates to the use of compositions comprising nomegestrol acetate (NOMAC) and estradiol or an ester thereof. The compositions are for use in reducing the risk of venous thromboembolism (VTE) associated with the use of combined oral contraceptives (COC). The compositions may be used in methods of contraception and/or methods of treatment in women having conditions linked to menstruation and/or fertility.

FIELD OF THE INVENTION

The present invention relates to the use of compositions comprisingnomegestrol acetate (NOMAC) and estradiol or an ester thereof. Thecompositions are for use in reducing the risk of venous thromboembolism(VTE) associated with the use of combined oral contraceptives (COC). Thecompositions may be used in methods of contraception and/or methods oftreatment in women having conditions linked to menstruation and/orfertility.

BACKGROUND TO THE INVENTION

Combined oral contraceptives (COCs), also known as combined hormonalcontraceptives (CHCs), are used to control the menstrual cycle of women.COC use in women typically prevents ovulation, and is thus a means toprevent pregnancy. COCs are a popular form of birth control and aretaken by over 100 million women worldwide. COCs are also used in aclinical setting to treat a range of disorders or conditions linked tomenstruation and fertility. Examples include the reduction of heavymenstrual bleeding, regulation of the menstrual cycle, alleviation ofdysmenorrhea, treatment of polycystic ovary syndrome, treatment ofhirsutism and treatment of premenstrual syndrome (Carey and Allen, TheObstetrician & Gynaecologist 2012; 14: 223-228).

COCs typically include an estrogen and a progestogen. A variety ofdifferent combinations of estrogens and progestogens are used indifferent COCs. Examples of different progestogens used in COCscurrently on the market are levonorgestrel, norethisterone, desogestrel,gestodene, cyproterone acetate, drospirenone, dienogest and nomegestrolacetate. Examples of different estrogens used in COCs currently on themarket are ethinylestradiol, mestranol, estradiol valerate andestradiol.

A significant problem associated with the use of COCs is increased riskof venous thromboembolism (VTE); VTE is one of the most serious adverseevents (AEs) associated with COC use (World Health OrganisationCollaborative Study of Cardiovascular Disease and Steroid HormoneContraception, The Lancet. (1995) 346: 1575-82; Practice Committee ofthe American Society for Reproductive Medicine, Fertility and Sterility.(2016) 107(1): 43-51; Dragoman et al., Int. J. Gynaecol Obstet. (2018)141(3): 287-294; see also:https://www.ema.europa.eu/en/human-regulatory/post-authorisation/referral-procedures/combined-hormonal-contraceptives).

VTE is characterised by a series of events whereby a blood clot or“thrombus” forms in a vein, a portion of the clot breaks away and iscarried in the circulation to a distal site where it lodges and causes ablockage in a blood vessel. A pulmonary embolism describes blockage inone of the pulmonary arteries in the lungs caused by a blood clot thathas travelled from a vein at a distal site, typically a deep vein of thelegs.

Taking into account the above, there is clearly a need to identifycompositions that are able to reduce the risk of VTE associated with theuse of COC use in woman. The present invention addresses this need, asexplained in more detail below.

SUMMARY OF INVENTION

One example of a COC already in clinical use is “NOMAC-E2”, a COCmarketed by Theramex HQ UK Limited as ZOELY®. NOMAC-E2 is a monophasicoral contraceptive containing a fixed dose of nomegestrol acetate (2.5mg) and 17β-estradiol (1.5 mg). NOMAC-E2 pills are typically taken bywomen for 24 days followed by 4 days of placebo.

The progestogen contained in NOMAC-E2, nomegestrol acetate or “NOMAC”,is a derivative of 19-norprogesterone and is thus structurally verysimilar to the naturally-occurring progesterone produced by the humanbody. It has a strong affinity for the progesterone receptor and hasstrong anti-gonadotropic activity and progesterone receptor-mediatedanti-estrogenic activity. It also has moderate anti-androgenic activity,and is devoid of estrogenic, androgenic, glucocorticoid ormineralocorticoid activity.

The estrogen contained in NOMAC-E2 is 17β-estradiol or “E2”. E2 is asynthetically produced estrogen but is identical to the naturalestrogen—17β-estradiol—produced by the human body; it is classified as a“bio-identical” hormone.

The present application reports the results of a study in which NOMAC-E2was found to reduce the risk of VTE when tested alongside comparatorCOCs. The comparator COCs contained the synthetic progesteronelevonorgestrel (LNG) and the synthetic estrogen ethinylestradiol.NOMAC-E2 has been in clinical use for some time without any serioushealth concerns. However, the present application reveals, for the firsttime, the opportunity to use COCs containing NOMAC and estradiol toreduce the risk of VTE in those women who are prescribed COC medication,for contraceptive use or otherwise.

In a first aspect, the present invention provides a composition for usein reducing the risk of venous thromboembolism (VTE) associated with theuse of combined oral contraceptives, wherein the composition comprisesnomegestrol acetate and estradiol or an ester thereof. The inventionalso provides a method of reducing the risk of venous thromboembolism(VTE) associated with the use of combined oral contraceptives, whereinthe method comprises administering to a woman a composition comprisingnomegestrol acetate (NOMAC) and estradiol or an ester thereof.

In a further aspect, the invention provides use of a compositioncomprising nomegestrol acetate and estradiol or an ester thereof as acontraceptive; wherein the risk of venous thromboembolism (VTE)associated with the use of combined oral contraceptives is reduced.

The invention also provides a method of contraception, wherein themethod comprises administering to a woman a composition comprisingnomegestrol acetate and estradiol or an ester thereof, wherein the riskof venous thromboembolism (VTE) associated with the use of combined oralcontraceptives is reduced in the woman administered the composition.

In a further aspect, the invention provides a method of treating acondition selected from: painful menstrual bleeding; heavy and/orprolonged menstrual bleeding; acne; ovarian cysts; polycystic ovarysyndrome (PCOS); premenstrual syndrome (PMS); endometriosis; andpremenstrual dysphoric disorder (PMDD), wherein the method comprisesadministering to a woman a composition comprising nomegestrol acetateand estradiol or an ester thereof, wherein the risk of venousthromboembolism (VTE) associated with the use of combined oralcontraceptives is reduced in the woman administered the composition.

The invention also provides a composition for use in a method oftreating a condition selected from: painful menstrual bleeding; heavyand/or prolonged menstrual bleeding; acne; ovarian cysts; polycysticovary syndrome; premenstrual syndrome; endometriosis; and premenstrualdysphoric disorder, wherein the composition comprises nomegestrolacetate and estradiol or an ester thereof; and wherein the risk ofvenous thromboembolism associated with the use of combined oralcontraceptives is reduced.

In preferred embodiments of all aspects of the invention describedherein, the composition comprises nomegestrol acetate and 17β-estradiol.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows an overview of cohorts included in the clinical studycategorised according to age group.

FIG. 2 shows the incidence of serious adverse effects (SAEs) observed inthe study—according to COC or contraceptive used.

FIG. 3 shows the incidence of deep vein thrombosis (DVT) of the lowerextremities and pulmonary embolism (PE). The incidence rates per 10,000WY and 95% confidence intervals per (sub)-cohort are shown.

FIG. 4 shows deep vein thrombosis (DVT) of the lower extremities andpulmonary embolism (PE) among women without known pre-defined riskfactors at baseline. The incidence rates per 10,000 WY and 95%confidence intervals per (sub)-cohort are shown.

FIG. 5 shows deep vein thrombosis (DVT) of the lower extremities andpulmonary embolism (PE) among women using a COC for contraceptivereasons only. The incidence rates per 10,000 WY and 95% confidenceintervals per (sub)-cohort are shown.

FIG. 6 shows deep vein thrombosis (DVT) of the lower extremities andpulmonary embolism (PE) excluding women recruited to the study fromRussia. The incidence rates per 10,000 WY and 95% confidence intervalsper (sub)-cohort are shown.

FIG. 7 shows all instances of venous thromboembolism (VTE), in which theincidence rates per 10,000 WY and 95% confidence intervals per(sub)-cohort are shown.

DETAILED DESCRIPTION A. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one skilled in theart in the technical field of the invention.

“Venous thromboembolism” (VTE)—as used herein the term “venousthromboembolism” or “VTE” is used to describe a series of events inwhich:

-   -   a blood clot (also known as a thrombus) forms in a vein;    -   the blood clot or a fragment thereof dislodges from the original        site of formation;    -   the blood clot or fragment thereof is transported via the        circulatory system to another blood vessel    -   the blood clot or fragment thereof lodges in the other blood        vessel, thereby causing a partial or total blockage of the blood        flow in the affected vessel.

There are a number of risk factors associated with the development ofVTE. The use of hormone-based medicines is associated with an increasedVTE risk. Hormone-based medicines include, for example, oralcontraceptives and hormone replacement therapies for women.

“Deep vein thrombosis”—as used herein the term “deep vein thrombosis” or“DVT” is used to describe a thrombus that forms in the deep veins of thelegs, groin or arms. Symptoms associated with DVT are pain or tendernessin the arms or legs (typically in the thigh or calf), swollen legs orarms, skin that is red or warm to the touch, red streaks on the skin ora change in colour of the skin.

“Pulmonary embolism”—as used herein the term “pulmonary embolism” or“PE” is used to refer to a blood clot or thrombus that has travelled tothe lungs from a distal site in the circulation and is blocking orpartially blocking a blood vessel of the lungs. Symptoms associated withPE are a sudden unexplained shortness of breath, rapid breathing, suddenunexplained coughs, sharp chest pain, rapid or irregular heart rate,light-headedness and severe pain in the stomach.

“Combined oral contraceptive” (COC)—as used herein a “combined oralcontraceptive” or “COC” refers to a hormonal combination treatment forwomen that includes an estrogen and a progestogen. Combined oralcontraceptives are also referred to in the literature as “combinedhormonal contraceptives” or “CHCs”. A variety of different combinationsof estrogens and progestogens are known to be used in different forms ofCOCs. The COCs for use according to the present invention comprisenomegestrol acetate (NOMAC) as the progestogen and estradiol or an esterthereof as the estrogen.

“Progestogens”—as used herein the term “progestogens” refers to a classof synthetic steroid hormones which produce similar or equivalenteffects to progesterone—the naturally occurring progestogen.Progestogens are also referred to as “gestagens”. Progestogens possessantiestrogenic and antigonadotropic properties. Many examples ofprogestogens are derivatives or metabolites of the naturally-occurringprogesterone.

“Nomegestrol acetate”—as used herein “nomegestrol acetate” or “NOMAC” or“NOMAc” refers to a kind of progestogen as represented by the formula:

NOMAC is also known as 17α-acetoxy-6-methyl-δ6-19-norprogesterone or as17α-acetoxy-6-methyl-19-norpregna-4,6-diene-3,20-dione. It is aderivative of progesterone belonging to the 19-norprogesterone and17α-hydroxyprogesterone groups.

“Estrogens”—as used herein the term “estrogens” (also written as“oestrogens”) refers to a class of steroid hormones of which theendogenous or naturally-occurring forms are estrone (E1), estradiol(E2), estriol (E3) and estetrol (E4). Estrogens perform a multitude offunctions within the human body including regulation of the menstrualcycle, ovulation and fertility.

“Estradiol”—as used herein the term “estradiol” or “E2” refers to theestrogen as represented by the formula:

This compound is also known as “17β-estradiol” or “beta-estradiol”.Estradiol is the predominant estrogen produced by the human body duringa woman's reproductive years.

“Woman of child-bearing age”—as used herein this term refers to apost-pubescent and pre-menopausal woman. A woman of child-bearing age isa woman who is most likely to use the compositions described herein as ameans of contraception.

“Means of contraception”—as used herein this term refers to the use of acomposition as described herein for the prevention of pregnancy.

“Non-contraceptive use”—as used herein this term refers to the use of acomposition as described herein for a purpose other than the preventionof pregnancy.

“Woman identified as at increased risk of VTE”—as used herein this termrefers to a woman who is classified as at higher risk of VTE on thebasis of having one or more risk factors known to predispose women toVTE.

“Body mass index” (BMI)—as used herein this term refers to the body massof an individual divided by the square of their body height and isuniversally expressed in units of kg/m². According to the World HealthOrganisation (WHO), an individual with a BMI value of above 30 (>30) isclassed as obese. Obesity is a condition in which the excess body fat ofan individual has accumulated to such an extent that it can have anegative impact on the health of the individual.

“Hazard Ratio” (HR)—as used herein the “hazard ratio” or “HR” is theratio of VTE risk in a first group of subjects versus the VTE risk in asecond group of subjects. The HR as described herein typicallyrepresents the VTE risk associated with women receiving compositions asdescribed herein (comprising NOMAC and estradiol or an ester thereof) ascompared with the VTE risk associated with women receiving a differentCOC. HRs may be calculated and expressed in crude form—by simplycomparing the incidence of VTE between two groups of subjects. HRs mayalso be calculated and expressed in an adjusted form, whereby the HR isadjusted to take into account other known VTE risk factors such as age,body mass index (BMI) at baseline, duration of use of the COC and familyhistory of VTE, in the two groups of subjects.

“Plain tablet” as used herein the term “plain tablet” refers to a solidcomposition that is compressed or otherwise formed into a defined shapeand quantity.

“Film-coated tablet”—as used herein the term “film-coated tablet” refersto a tablet encapsulated by a polymer-based coating. The coating may beused to prevent the tablet from degrading in the stomach.

“Sugar-coated tablet”—as used herein the term “sugar-coated tablet”refers to a tablet encapsulated by a mono-, di-, oligo- orpoly-saccharide coating. The coating may be used to mask the flavour ofparticularly unpalatable drugs. The coating can also be used to preventlight or moisture from entering the tablet, which could prevent a drugfrom breaking down prematurely.

“Soft gelatin capsule”—as used herein the term “soft gelatin capsule”refers to a dosage form in which a liquid or semi-solid centre (innerfill) is encapsulated by a solid capsule (outer shell). The outer shellmay comprise, for example, a combination of gelatin, water, opacifierand a plasticizer such as glycerin and/or sorbitol(s).

“Cachets” or “wafer capsules”—as used herein, these terms refer to aseal-shaped capsule or wafer made of flour for enclosing powders ofdisagreeable taste. The sealed dosage form is wetted and swallowed.

“Pill”—as used herein this term refers to any solid form of medication.

“Powder”—as used herein this term refers to a mixture of solidnon-compressed, active drug (e.g. NOMAC-E2) and excipients.

“Excipient”—as used herein this term refers to a compound that isgenerally safe, non-toxic and neither biologically nor otherwiseundesirable. The excipient is substantially inert.

“Oral administration”—as used herein this term means that the dosageform is taken by mouth and is thereby delivered into thegastrointestinal tract.

“Monophasic”—as used herein this term means that a fixed quantity ordosage of the estrogen and/or the progestogen in the COC is administeredthroughout a treatment cycle. For example, if a treatment cycle consistsof 24 daily doses of the COC, a fixed quantity or dosage of the estrogenand/or the progestogen is administered to the woman each day of the24-day 25 period. The NOMAC-E2 compositions described herein may beadministered as monophasic oral contraceptives. For example, a fixeddosage of 2.5 mg and 1.5 mg E2 may be administered daily for a period of24 days.

“Multiphasic”—as used herein this term means that the quantity or dosageof the estrogen and/or the progestogen varies throughout a treatmentcycle. For example, if a treatment cycle consists of daily doses of aCOC over a period of several days, the amount of estrogen and/orprogestogen administered to the woman on different days of the treatmentcycle can vary.

“Acne”—as used herein this term refers to a long-term skin disease thatoccurs when dead skin cells and oil from the skin clog hair follicles.Typical features of the condition include blackheads or whiteheads,pimples, oily skin, and possible scarring.

“Ovarian cysts”—as used herein this term refers to fluid-filled sacsthat develop in or on the ovaries. Typically, an ovarian cyst onlycauses symptoms if it ruptures, is very large or blocks the blood supplyto the ovaries. Symptoms associated with ovarian cysts are pelvic pain,pain during sex, difficulty emptying the bowels, a frequent need tourinate, heavy periods, irregular periods, lighter periods than normal,bloating or a swollen stomach, feeling very full after only eating alittle and difficulty getting pregnant.

“Polycystic ovary syndrome” (PCOS)—as used herein this term refers to acondition in which the ovaries contain a large number of follicles. Thefollicles are underdeveloped sacs in which eggs develop, which meansthat these sacs are often unable to release an egg. PCOS can result in alack of ovulation and problems with fertility. Symptoms of PCOS includeirregular periods or no periods at all, difficulty getting pregnant,excessive hair growth (hirsutism), (particularly on the face, chest,back or buttocks), weight gain, thinning hair and hair loss from thehead, oily skin or acne.

“Premenstrual syndrome” (PMS)—as used herein this term refers to arecurring, cyclical disorder involving behavioural, emotional, socialand physical symptoms (Steiner et al., Annu. Rev. Med. (1997) 48:447-455). Symptoms may include, irritability, mood swings, depression,hostility and social withdrawal. Physical symptoms include, bloating,breast tenderness, myalgia, migraines, headaches, or fatigue.

“Endometriosis”—as used herein this term refers to a condition wheretissue similar to the lining of the womb starts to grow elsewhere in thereproductive system, such as the ovaries and fallopian tubes. Symptomsmay include any one or more of: abdominal pain, back pain, period pain,pain during or after sex, pain during defecation or urination, feelingsick, constipation, diarrhoea, blood in the stool, difficulty gettingpregnant, heavy periods or depression.

“Premenstrual dysphoric disorder” (PMDD)—as used herein this term refersto a disorder possessed by a subgroup of women with PMS. PMDD isconsidered a severe form of PMS. Symptoms can include any one or moreof: mood swings, feeling upset or tearful, feeling angry or irritable,feelings of anxiety, feeling hopeless, feelings of tension or being onedge, difficulty concentrating, feeling overwhelmed, lack of energy,less interest in activities normally enjoyed, suicidal feelings, breasttenderness or swelling, pain in your muscles and joints, headaches,feeling bloated, changes in appetite or sleep problems.

“Menstrual cycle regulation”—as used herein this term refers to theregulation of the menstrual cycle using hormonal treatment. Hormonaltreatments may be used to regulate the menstrual cycle in women whoexhibit problems including but not limited to menstrual cycles ofdiffering length, painful menstruation, very heavy bleeding atmenstruation.

“Placebo”—as used herein refers to a dosage form containing no activeingredient.

B. Compositions and Methods for Reducing the Risk of VenousThromboembolism (VTE)

As discussed herein, the use of COCs has been connected with an increasein the risk of blood clots in the veins or “venous thromboses” andconsequently an increase in the risk of VTE.

Typically, about 2 out of 10,000 women who are not using a COC and arenot pregnant develop a blood clot in a vein in a year. In contrast,about 5-7 out of 10,000 women using a COC containing levonorgestrel,norethisterone or norgestimate develop a blood clot in a vein in a year.The incidence increases to about 6-12 out of 10,000 women using a COCcontaining etonogestrel or norelgestromin and about 9-12 out of 10,000women using a COC containing drospirenone, gestodene or desogestrel (seehttps://www.ema.europa.eu/en/human-regulatory/post-authorisation/referral-procedures/combined-hormonal-contraceptives).

As reported herein, it has unexpectedly been found that women taking aCOC containing NOMAC and estradiol exhibit a reduced risk of VTE. Thisreduction in risk was seen relative to women taking other COCscontaining different forms of progestogen and estrogen. Women taking aCOC containing NOMAC and estradiol developed VTE, as measured by acombination of DVT of the lower extremities and PE, at a rate of 1.5 per10,000 women years. In contrast, women taking a COC containinglevonorgestrel (COC_(LNG)) developed VTE, as measured by a combinationof DVT of the lower extremities and PE, at a rate of 2.6 per 10,000women years. Furthermore, women taking other forms of COC containingdifferent estrogens and/or progestogens developed VTE at a rate of 6.7per 10,000 women years.

Taking into account the above, in a first aspect, the invention providesa composition for use in reducing the risk of venous thromboembolism(VTE) associated with the use of combined oral contraceptives (COCs),wherein the composition comprises NOMAC and estradiol or an esterthereof.

The invention provides, in a further aspect, a method of reducing therisk of venous thromboembolism (VTE) associated with the use of combinedoral contraceptives (COCs), wherein the method comprises administeringto a woman or women a composition comprising NOMAC and estradiol or anester thereof.

All embodiments described herein below are equally applicable to thecompositions for use and methods of reducing the risk of VTE accordingto these aspects of the invention.

(i) Reducing the Risk of VTE

The compositions for use and methods in accordance with these aspects ofthe invention are aimed at reducing the risk of VTE associated with theuse of COCs. As described herein, a significant decrease in theincidence of VTE was observed in women taking a COC containing NOMAC andestradiol as compared with women taking other forms of COC. The risk ofVTE associated with the use of COCs is thus clearly reduced in womentaking compositions comprising NOMAC and estradiol or esters thereof.

In some embodiments, a reduced risk of VTE manifests as a reducedincidence or risk of “idiopathic VTE”. Idiopathic VTE is also known as“unprovoked VTE” or “spontaneous VTE”. Idiopathic VTE encompasses allforms of VTE that are not associated with temporary risk factors;temporary risk factors include but are not limited to pregnancy,delivery, trauma, immobilization, long-haul travel, surgery andchemotherapy.

In some embodiments, a reduced risk of VTE manifests as a reducedincidence or risk of deep vein thrombosis (DVT). In some embodiments, areduced risk of VTE manifests as a reduced incidence or risk ofpulmonary embolism (PE). In some embodiments, a reduced risk of VTEmanifests as a reduced incidence or risk or DVT and PE. As describedabove, DVT and PE are both common occurrences in the chain of eventsassociated with VTE and thus a reduction in the incidence or risk of oneor both of these occurrences is directly linked to a reduced risk ofVTE.

The invention provides compositions for use and methods wherein the riskof VTE associated with the use of COCs is reduced. As noted above, COCuse by women results in an elevated risk of VTE as compared with the VTErisk in women who are not taking any form of COC. For example, the riskof DVT in women taking COCs is increased from about 2 out of 10,000women in a year to anywhere between 5 and 12 out of 10,000 women in ayear (depending on the active ingredients).

The risk of VTE associated with compositions used in accordance with theinvention is reduced relative to the elevated risk observed in womentaking COCs i.e. the level of risk associated with the use of COCsgenerally. In certain embodiments, the risk is reduced as compared withthe risk observed in women taking COCs (of any type) by at least 10%, atleast 20%, at least 30%, at least 40%, or at least 50%.

In some embodiments, the risk of VTE associated with compositions usedin accordance with the invention is reduced relative to the risk of VTEassociated with the use of a particular COC, specifically a differentCOC. In this regard, a different COC means a COC other than acomposition for use in accordance with the invention as defined herein.A different COC will not contain NOMAC and estradiol or an esterthereof.

In some embodiments, the risk of VTE is reduced relative to the riskassociated with use of a different COC containing different forms ofestrogen and/or progestogen as compared with the compositions describedherein. The different COC may comprise a synthetic estrogen selectedfrom the group including but not limited to ethinylestradiol, ormestranol. Alternatively or in addition, the different COC may comprisea synthetic progestogen selected from the group including but notlimited to levonorgestrel, norethisterone, desogestrel, gestodene,cyproterone acetate, drospirenone, or dienogest.

In some embodiments, the risk of VTE is reduced relative to the riskassociated with use of a COC containing a progestogen selected fromnorethisterone, levonorgestrel or desogestrel. As reported in PracticeCommittee of the American Society for Reproductive Medicine, Fertilityand Sterility. (2016) 107(1): 43-51 (the contents of which areincorporated herein in their entirety), the relative risk associatedwith women using COCs containing norethisterone, levonorgestrel ordesogestrel is: 3.2; 2.8; or 3.8, respectively. This relative risk isexpressed relative to the risk of VTE in non-pregnant women, not takingany hormone treatment. The relative risk of VTE associated withcompositions used in accordance with the invention may be reduced by atleast 10%, at least 20%, at least 30%, at least 40%, or at least 50% ascompared with the relative risk observed in women using COCs containingnorethisterone, levonorgestrel and/or desogestrel.

In some embodiments, the risk of VTE associated with compositions usedin accordance with the invention is reduced relative to the riskassociated with use of a COC containing the progestogenlevonorgestrel—also referred to herein as COC_(LNG). In someembodiments, the risk of VTE is reduced relative to the risk associatedwith use of a COC containing levonorgestrel and ethinylestradiol.

In some embodiments, the risk of VTE is reduced relative to a monophasicCOC containing levonorgestrel. In some embodiments, the risk of VTE isreduced relative to a monophasic COC containing levonorgestrel and 20-30mcg ethinylestradiol. In some embodiments, the risk of VTE is reducedrelative to a monophasic COC containing levonorgestrel and 20 mcgethinylestradiol. In some embodiments, the risk of VTE is reducedrelative to a multiphasic COC containing levonorgestrel. In otherembodiments, the risk of VTE is reduced relative to a multiphasic COCcontaining levonorgestrel and 40 mcg ethinylestradiol. The dose oflevonorgestrel in the COC may be in the range from 100 mcg to 250 mcg.In certain embodiments, the dose of levonorgestrel in the COC is 150mcg.

The reduction in risk of VTE associated with compositions used inaccordance with the invention may be expressed as a Hazard Ratio (HR).In some embodiments, the HR associated with use of the compositionsdescribed herein is 0.3-0.6. In some embodiments, the HR associated withuse of the compositions described herein is 0.5-0.7. In someembodiments, the HR is 0.5-0.6. In some embodiments, the HR is 0.5. Insome embodiments, the crude HR (HR_(crude)) is 0.5. In other embodimentsthe adjusted HR (HR_(adj)) is 0.5. In other embodiments, the HR is 0.6.In some embodiments, the crude HR (HR_(crude)) is 0.6. In otherembodiments the adjusted HR (HR_(adj)) is 0.6.

As described herein, the crude HR can be adjusted to take into accountother known VTE risk factors. These risk factors include, for example,BMI at baseline in the two groups of subjects. In some embodiments, theadjusted HR takes into account the actual BMI at baseline. In otherembodiments, the adjusted HR takes into account an imputed BMI atbaseline (i.e. in which missing BMI values were imputed). In theseembodiments, the adjusted HR is 0.5.

In some embodiments, the risk of VTE is reduced relative to a monophasicCOC containing levonorgestrel and 20 mcg ethinylestradiol and theHR_(crude) is 0.4. In other embodiments, the risk of VTE is reducedrelative to a monophasic COC containing levonorgestrel and 20 mcgethinylestradiol and the HR_(adj) is 0.3. In some embodiments, the riskof VTE is reduced relative to a multiphasic COC containinglevonorgestrel and 40 mcg ethinylestradiol and the HR_(crude) is 0.5. Inother embodiments, the risk of VTE is reduced relative to a multiphasicCOC containing levonorgestrel and 40 mcg ethinylestradiol and theHR_(adj) is 0.4.

In some embodiments, the risk of VTE associated with compositions usedin accordance with the invention is reduced by at least 10%, at least20%, at least 25%, at least 30%, at least 40% as compared with the riskassociated with COC use in women.

In some embodiments, the risk of VTE is reduced by at least 20% in womenadministered compositions comprising NOMAC and estradiol or an esterthereof as compared with women taking COC_(LNG). In some embodiments,the risk of VTE is reduced by at least 25% in women administeredcompositions comprising NOMAC and estradiol or an ester thereof ascompared with women taking COC_(LNG). In some embodiments, the risk ofVTE is reduced by at least 30% in women administered compositionscomprising NOMAC and estradiol or an ester thereof as compared withwomen taking COC_(LNG). In some embodiments, the risk of VTE is reducedby at least 35% in women administered compositions comprising NOMAC andestradiol or an ester thereof as compared with women taking COC_(LNG).

In preferred embodiments, the risk of VTE is reduced by at least 40% inwomen administered compositions comprising NOMAC and estradiol or anester thereof as compared with women taking COC_(LNG). In furtherpreferred embodiments, the risk of VTE is reduced by 50% or halved inwomen administered compositions comprising NOMAC and estradiol or anester thereof as compared with women taking COC_(LNG).

(ii) Administration to Women

VTE can affect men and women of all ages, races and ethnicities. Thecurrent invention is concerned with the use of compositions comprisingNOMAC and estradiol or an ester thereof in reducing the risk of VTEassociated with the use of COCs. As described herein, COCs are used forboth contraceptive and non-contraceptive uses in women and therefore,the compositions comprising NOMAC and estradiol or an ester thereof asdescribed herein are typically administered to a woman or women so as toreduce the elevated VTE risk linked to COC use.

In some embodiments, the compositions as described herein areadministered to a woman or women of child-bearing age. Accordingly, insome embodiments, the compositions are administered to a woman or womenaged 12-55. In some embodiments, the woman or women is/are aged 15-55.In some embodiments, the woman or women is/are aged 15-50. In someembodiments, the woman or women is/are aged 15-45.

In certain embodiments, the compositions as described herein areadministered as a means of contraception.

Whilst the majority of women take COCs for contraceptive purposes, COCsmay also be prescribed for non-contraceptive uses. Accordingly, incertain embodiments, a composition as described herein is administeredto a woman or women for a non-contraceptive use.

The non-contraceptive use may be prevention or treatment of a conditionselected from: painful menstrual bleeding; heavy and/or prolongedmenstrual bleeding; acne; ovarian cysts; polycystic ovary syndrome(PCOS); premenstrual syndrome (PMS); endometriosis; and premenstrualdysphoric disorder (PMDD).

In some embodiments, a composition as described herein is administeredto a woman or women so as to prevent or treat one or more, two or more,three or more, four or more, five or more conditions selected from:painful menstrual bleeding; heavy and/or prolonged menstrual bleeding;acne; ovarian cysts; polycystic ovary syndrome (PCOS); premenstrualsyndrome (PMS); endometriosis; and premenstrual dysphoric disorder(PMDD).

In some embodiments, a composition as described herein is administeredto a woman or women for the purposes of menstrual cycle regulation. Thecomposition may be administered to normalise the duration of themenstrual cycle in a woman or women having irregular menstrual cyclelengths.

Alternatively or in addition, the composition may be administered tonormalise the frequency of ovulation in a woman or women havingirregular patterns of ovulation.

Since the compositions described herein are associated with a reducedrisk of VTE as compared with the elevated risk seen in women takingother forms of COC, they are particularly effective for use in women whomay be at increased risk of VTE linked to COC use. Certain groups ofwomen are also known to be at increased risk of developing VTE per se ascompared with the general population or with the risk seen in womengenerally. Accordingly, in certain embodiments, a composition asdescribed herein is administered to a woman or women classified as atincreased risk of VTE. A woman or women classified as “at increased riskof VTE” may have an increased risk of VTE that is independent of theelevated VTE risk associated with COC use.

In some embodiments, a composition as described herein is administeredto a woman or women 35 years of age or above; optionally 36 years of ageor above; optionally 37 years of age or above; optionally 38 years ofage or above; optionally 39 years of age or above; optionally 40 yearsof age or above. The composition may be administered to a woman or womenhaving an age of between 35 and 45.

In some embodiments, a composition as described herein is administeredto an overweight woman or to overweight women. In some embodiments, acomposition as described herein is administered to an obese woman or toobese women. In some embodiments, a composition as described herein isadministered to a woman or women having a BMI of >23 kg/m². In someembodiments, a composition as described herein is administered to awoman or women having a BMI of >25 kg/m². In some embodiments, acomposition as described herein is administered to a woman or womenhaving a body mass index (BMI)>30 kg/m². In some embodiments, acomposition as described herein is administered to a woman or womenhaving a BMI >35 kg/m². In some embodiments, a composition as describedherein is administered to a woman or women having a BMI >40 kg/m². Insome embodiments, a composition as described herein is administered to awoman or women having a BMI of 30 kg/m² to 35 kg/m².

In some embodiments, a composition as described herein is administeredto a woman or women who are categorised as overweight or obese accordingto one or measures used in clinical practice.

In some embodiments, a composition as described herein is administeredto a woman or women who have hypertension or who have a history ofhypertension (for example during pregnancy).

In some embodiments, a composition as described herein is administeredto a woman or women who is/are smokers.

In some embodiments, a composition as described herein is administeredto a woman or women with diabetes.

In some embodiments, a composition as described herein is administeredto a woman or women having a condition selected from: cancer; systemiclupus erythematosus (SLE); haemolytic uraemic syndrome; chronicinflammatory bowel disease (such as Crohn's disease or ulcerativecolitis); and sickle cell disease.

In some embodiments, the composition is administered to a woman or womenhaving cancer. The cancer may be selected from breast cancer or cervicalcancer.

In some embodiments, the composition is administered to a woman or womenpostpartum. The risk of VTE is significantly increased in pregnant andpostpartum women. For example, incidence rates typically rise to5-20/10,000 women years in pregnancy and 40-65/10,000 women yearspostpartum (see Practice Committee of the American Society forReproductive Medicine, Fertility and Sterility. (2016) 107(1): 43-51).In some embodiments, the composition is administered to a woman or womenwho are breastfeeding 6 weeks to 6 months postpartum. In someembodiments, the composition is administered to a woman or women who arenot breastfeeding 3 weeks to 6 weeks postpartum.

In certain embodiments, a composition as described herein isadministered to a woman or women having a family history of VTE(especially VTE in a parent or sibling). Alternatively or in addition, awoman or women administered a composition as described herein may havean acquired predisposition for VTE, for example by virtue of having acondition that affects blood clotting. Non-limiting examples ofconditions that affect blood clotting are protein C deficiency,antithrombin III deficiency, Factor V Leiden thrombophilia andantiphospholipid syndrome (APS).

In further embodiments, a composition as described herein isadministered to a woman or women who have undergone major surgery. Thiscould include but is not limited to surgery to the legs or pelvis,neurosurgery, or major trauma.

In further embodiments, a composition as described herein isadministered to a woman or women who exhibit long-term immobility, forexample by virtue of wheelchair use.

In further embodiments, a composition as described herein isadministered to a woman or women who have had one or more previousoccurrences of deep vein thrombosis (DVT) and/or pulmonary embolism(PE). In other words, the woman or women may have a clinical historythat is indicative of an increased risk of VTE.

In some embodiments, a composition as described herein is administeredto a woman or women having a plurality of risk factors associated withincreased risk of developing VTE.

In some embodiments, a composition as described herein is administeredto a woman or women who has/have not received a prior COC. Inalternative embodiments, a composition as described herein isadministered to a woman or women who has/have previously received COCtreatment in their lifetime. Such women may be classified as“restarters”. Such women may have taken a break from COC treatment for aperiod of 2 months or more, 3 months or more, 4 months or more, 5 monthsor more, 6 months or more, 12 months or more. As reported herein, therisk of VTE, as measured by DVT of the lower extremities and PE, can beparticularly high in women restarting COC treatment—see Table 7, whichreports an incidence of 4.8 in women restarting COC_(LNG) use ascompared with an incidence of 2.6 for the total population of womenreceiving COC_(LNG). Significantly, this increase in VTE risk was notseen in restarters administered NOMAC-E2—an incidence of 1.7 wasobserved in women restarting NOMAC-E2 as compared with an incidence of1.5 for the total population of women receiving NOMAC-E2. This indicatesthat the compositions for use as described herein are particularlyeffective at reducing VTE risk in women who have previously received COCtreatment.

In some embodiments, a composition as described herein is administeredto a woman or women who has/have previously received a COC that does notcontain NOMAC and estradiol or an ester thereof.

(iii) Compositions Comprising NOMAC and Estradiol or an Ester Thereof

The compositions described herein for use in accordance with theinvention comprise NOMAC and estradiol or an ester thereof. Thecompositions for use in accordance with the invention are thusthemselves COCs wherein the progestogen active ingredient is NOMAC andthe estrogen active ingredient is estradiol or an ester thereof. Asdescribed elsewhere herein, these compositions are associated with areduced risk of VTE and can thus be used in place of other COCs so as toreduce the risk of VTE associated with COC use in women.

In some embodiments, the NOMAC and estradiol or ester thereof arepresent in a weight ratio of 5 to 0.5. In some embodiments, the NOMACand estradiol or ester thereof are present in a weight ratio of 3 to 1.In a preferred embodiment, the NOMAC and estradiol or ester thereof arepresent in a weight ratio of 1.67 to 1.

In some embodiments, the NOMAC is present in an amount ranging from 1.5mg to 3.75 mg. In some embodiments, the estradiol or ester thereof ispresent in an amount ranging from 0.5 mg to 3 mg. In some embodiments,the NOMAC is present in an amount of about 2.5 mg and the estradiol orester thereof is present in an amount of about 1.5 mg.

In a preferred embodiment, the NOMAC is present in an amount of 2.5 mgand the estradiol or ester thereof is present in an amount of 1.5 mg.

In some embodiments, the compositions for use comprise NOMAC incombination with an estradiol ester. Such estradiol esters include butare not limited to estradiol valerate, estradiol benzoate, estradiolphenylpropionate, estradiol enanthate, estradiol acetate, estradiolcypionate, estradiol dipropionate, estradiol undecylate andpolyestradiol phosphate (an estradiol ester in polymeric form).

In preferred embodiments, the composition comprises NOMAC in combinationwith 17β-estradiol (also referred to herein as E2). In a particularlypreferred embodiment, the 17β-estradiol is in hemihydrate form. Inpreferred embodiments, the composition comprises 2.5 mg NOMAC and 1.5 mg17β-estradiol.

Without wishing to be bound by theory, it is thought that compositionscomprising NOMAC and 17β-estradiol might be associated with a reducedrisk of VTE since the progestogen and estrogen ingredients present inthese compositions are structurally very similar (in the case of NOMAC)and identical (in the case of 17β-estradiol) to the naturally-occurringforms of these hormones found in women.

The compositions for use according to the invention may be formulated soas to comprise one or more pharmaceutically acceptable carriers orexcipients. Alternatively or in addition, the compositions for useaccording to the invention may be formulated as to comprise one or moreadditional agents selected from but not limited to: binding agents;disintegrants; lubricants; glidants; fillers; and/or diluents.

In some embodiments, the composition comprises one or more additionalagents selected from: lactose monohydrate; anhydrous lactose;spray-dried lactose; sifted/sieved/milled lactose; crystalline lactose;sucrose; trehalose; dextrose; fructose; dextrates; dextrin; dextroseanhydrous; sorbitol; mannitol; xylitol; maltitol solution; glucoseliquid; and polydextrose.

Alternatively or in addition, the composition may comprise one or moreadditional agents selected from: microcrystalline cellulose; cellulosepowder or derivatives thereof with different molecular weights includingother forms such as gel, gum, crystal, cotton, sugar, alpha-grade,paste, guar gum; pre-gelatinised maize starch; croscarmellose sodium;alginic acid; acacia; calcium phosphate (dibasic anhydrous/dihydrate,tribasic); carboxymethylcellulose sodium; carrageenan; silicifiedmicrocrystalline cellulose; cellulose acetate; cellulose acetatephthalate; carbomer; hydroxypropyl cellulose (or low substituted);hydroxypropyl starch; hypromellose (and acetate succinate andphthalate); hydroxyethyl cellulose; hydroxyethylmethyl cellulose;hydroxypropyl cellulose; sodium phosphate (dibasic or monobasic); sodiumstarch glycolate; maize starch; sucralose; povidone; polyoxyethylen(including alkly ethers, castor oil derivatives, sorbitan fatty acidesters, stearate, glycerides); shellac; sodium alginate; vitamin Epolyethylene glycol succinate; calcium sulfate; carbomer (polyacrylicacid, carboxyvinyl polymer, carbopol); carrageenan; chitosan;hydroxypropyl starch; corn starch; pregelatinized starch; dextrates;dextrin; dextrose; glycerol behenate; Novagel®/Avicel® (such as PH 101,102, 301, 302); Vivapur®; Emcocel®; Comprecel®; and Microcel®.

Alternatively or in addition, the composition may comprise one or moreadditional agents selected from: crospovidone; PVP; polyvinylN-pyrrolidone; povidone, plasdon; polypasdone (including itsXL/XL-10/INF-10) with differing particle size distribution (standard,fine, superfine, micronized); guar gum; hydroxypropyl betadex;hydroxypropyl starch; sodium starch glycolate; Kollidon® (with fullrange of K value—PVP K12, PVP K15, PVP K17, PVP K30, PVP K60, PVP K90,bulk density, hydration capacity, and peroxide levels); andcroscarmellose sodium.

Alternatively or in addition, the composition may comprise one or moreadditional agents selected from: talc; magnesium silicate (monoclinic ortriclinic); aluminium magnesium silicate; talcum; corn starch; kaolin;saponite; montmorillonite; and titanium dioxide.

Alternatively or in addition, the composition may comprise one or moreadditional agents selected from: magnesium stearate (generally a mixtureof crystalline forms—anhydrate, monohydrate, dihydrate and trihydratewith Mg, Ca, Na); stearic acid; a composition consisting of magnesiumstearate to palmitate, and other fatty acid esters, such as palmiticacid, myristic acid, glyceride esters (glyceryl monostearate, glyceryltribehenate, glyceryl dibehenate or Compritol 888) and sugar esters(sorbitan monostearate and sucrose monopalmitate); sodium stearylfumarate; hydrogenated vegetable oil; hydrogenated castor oil; sterotex;talc; waxes (such as anionic emulsifying, carnauba, cetyl esters,microcrystalline, nonionic emulsifying, white or yellow); Stear-O-Wet;boric acid; carbowax (PEG) 4000/6000; sodium oleate; sodium benzoate;sodium acetate; sodium lauryl sulfate; and Mg-lauryl sulfate

Alternatively or in addition, the composition may comprise one or moreadditional agents selected from: colloidal anhydrous silica or silicondioxide colloidal; Aerosil; Cab-O-Sil; fumed silica; anhydrous silicicacid; silicic anhydride; silicon dioxide fumed; silicon dioxideamorphous; magnesium trisilicate; magnesium silicate; and magnesiumaluminium silicate.

In some embodiments, the composition comprises at least one additionalagent selected from: lactose monohydrate; microcrystalline cellulose;crospovidone; talc; magnesium stearate; and colloidal anhydrous silica;or any combination thereof.

In some embodiments, the composition comprises the additional agents:lactose monohydrate; microcrystalline cellulose; crospovidone; talc;magnesium stearate; and colloidal anhydrous silica.

In some embodiments, the composition comprises or consists of:

Constituent Amount (mg) NOMAC 1.5-3.5 17β-estradiol 0.5-2.5 lactosemonohydrate 15-98 microcrystalline cellulose  5-90 crospovidone 1-5 talc0.2-2  magnesium stearate 0.2-2  colloidal anhydrous silica 0.2-2 

In preferred embodiments, the composition comprises or consists of:

Constituent Amount (mg) NOMAC 2.5 17β-estradiol 1.5 lactose monohydrate57.7 microcrystalline cellulose 14 crospovidone 2.4 talc 0.7 magnesiumstearate 0.7 colloidal anhydrous silica 0.44

In preferred embodiments, the composition comprises or consists of:

Constituent Amount (mg) NOMAC 2.5 17β-estradiol hemihydrate 1.55*lactose monohydrate 57.7 microcrystalline cellulose 14 crospovidone 2.4talc 0.7 magnesium stearate 0.7 colloidal anhydrous silica 0.44*Equivalent to 1.5 mg estradiol

In some embodiments, the composition is formulated for oraladministration.

In some embodiments, the composition is in the form of plain orfilm-coated tablets, sugar-coated tablets, soft gelatin capsules, wafercapsules, pills, cachets or powders.

In preferred embodiments, the composition is in the form of afilm-coated tablet. In some embodiments, the film-coating comprises oneor more of: poly(vinyl alcohol); titanium dioxide; macrogol 3350; and/ortalc.

(iv) Administration Schedule

The compositions for use in accordance with the invention are, in someembodiments, administered at a frequency of once per day i.e. daily. Insome embodiments, the compositions are administered daily for a periodof between 21 and 28 days. In some embodiments, the compositions areadministered daily for a period of between 21 and 28 days per treatmentcycle. In some embodiments, the compositions are administered for aperiod of between 21 and 28 consecutive days per treatment cycle. Inother embodiments, the compositions are administered for a period of 21to 28 days intermittently per treatment cycle. In a preferredembodiment, the compositions are administered once a day for a period of24 consecutive days per treatment cycle.

The compositions may be administered once a day for a period of 24consecutive days followed by a hormone-free period of 4 consecutivedays. The compositions may administered once a day for a period of 24consecutive days followed by administration of a placebo tablet once aday for a period of 4 consecutive days. The administration of 24consecutive daily doses of the composition followed by 4 consecutivedaily doses of placebo may constitute one treatment cycle. One treatmentcycle may be followed directly by one or more consecutive treatmentcycles.

In preferred embodiments, the composition is administered as amonophasic composition for the duration of the period of administration.

(v) Pharmaceutical Kits

In some embodiments, the compositions for use as described herein, areprovided in the form of pharmaceutical kits, optionally wherein the kitscontain instructions for use.

A pharmaceutical kit may comprise a plurality of dosage units ofcompositions as described herein. The pharmaceutical kit may optionallyfurther comprise at least one placebo dosage unit.

In preferred embodiments, the pharmaceutical kits comprise or consist of24 dosage units of a composition as described herein and 4 dosage unitsof a placebo.

C. Uses and Methods of Contraception

In another aspect, the invention provides use of a compositioncomprising NOMAC and estradiol or an ester thereof as a contraceptive,wherein the risk of venous thromboembolism (VTE) associated with the useof combined oral contraceptives (COC) is reduced.

In a further aspect, the invention also provides a method ofcontraception, wherein the method comprises administering to a woman acomposition comprising NOMAC and estradiol or an ester thereof; andwherein the risk of VTE associated with the use of combined oralcontraceptives (COCs) is reduced in the woman administered thecomposition.

All embodiments described herein relating to the composition for useaccording to the preceding aspects of the invention (see in particular,Section B) are equally applicable to these further aspects of theinvention.

D. Methods of Treatment

In another aspect, the invention provides a method of treating acondition selected from: painful menstrual bleeding; heavy and/orprolonged menstrual bleeding; acne; ovarian cysts; polycystic ovarysyndrome (PCOS); premenstrual syndrome (PMS); endometriosis; andpremenstrual dysphoric disorder (PMDD), wherein the method comprisesadministering to a woman a composition comprising nomegestrol acetate(NOMAC) and estradiol or an ester thereof, wherein the risk of VTEassociated with the use of combined oral contraceptives (COCs) isreduced in the woman administered the composition.

In a further aspect, the invention provides a composition for use in amethod of treating a condition selected from: painful menstrualbleeding; heavy and/or prolonged menstrual bleeding; acne; ovariancysts; polycystic ovary syndrome (PCOS); premenstrual syndrome (PMS);endometriosis; and premenstrual dysphoric disorder (PMDD), wherein thecomposition comprises nomegestrol acetate (NOMAC) and estradiol or anester thereof; and wherein the risk of VTE associated with the use ofcombined oral contraceptives (COCs) is reduced.

In some embodiments, the condition is a menstrual disorder. In someembodiments, the condition is painful menstrual bleeding. In someembodiments, the condition is dysmenorrhea.

In some embodiments, the condition is heavy and/or prolonged menstrualbleeding. In some embodiments, the condition is metrorrhagia. In someembodiments, the condition is polymenorrhea. In some embodiments, thecondition is ovarian cysts. In some embodiments, the condition ispolycystic ovary syndrome (PCOS). In some embodiments, the condition ispremenstrual syndrome (PMS). In some embodiments, the condition isendometriosis.

In some embodiments, the condition is premenstrual dysphoric disorder(PMDD). In some embodiments, the condition is acne. In some embodiments,the condition is hirsutism.

All embodiments described herein relating to compositions for useaccording to the preceding aspects of the invention (see in particular,Section B) are equally applicable to these further aspects of theinvention.

INCORPORATION BY REFERENCE

Various publications are cited in the foregoing description andthroughout the following example, each of which is incorporated byreference herein in its entirety.

Example

The invention will be further understood with reference to the followingnon-limiting example.

Prospective, Controlled Cohort Study on the Safety of a Monophasic OralContraceptive Containing Nomegestrol Acetate (2.5 mg) and 17β-Estradiol(1.5 mg) (the PRO-E2 Study)

1. Summary

A large clinical study was conducted to evaluate the safety of amonophasic combined oral contraceptive (COC) containing nomegestrolacetate (NOMAC) and 17β-estradiol. This COC—referred to herein asNOMAC-E2—has been on the market for some time with no serious healthconcerns. However, this multinational, non-randomized, controlled,prospective, active surveillance study was conducted so to as monitorthe risk of rare serious adverse outcomes in a large cohort of womentaking NOMAC-E2 as compared with a large cohort of women taking a adifferent COC—referred to herein as COC_(LNG). The COC_(LNG) comparatorsused in this study are considered to be one of the CHCs associated withthe lowest risk of VTE in patients and because of this they aretypically used as first line CHCs.

The main clinical outcome of interest was venous thromboembolism (VTE),and specifically deep vein thrombosis (DVT) of the lower extremities andpulmonary embolism (PE).

The results presented herein are based on 91,313 women (44,559 NOMAC-E2users and 46,754 COC_(LNG) users) recruited between August 2014 andSeptember 2019. Starters (i.e. those women who had not received COCtreatment before) comprised 62.6% of NOMAC-E2 users and 64.4% ofCOC_(LNG) users. A total of 37.4% of NOMAC-E2 users and 35.6% ofCOC_(LNG) users were restarters (i.e. women who had received COCtreatment previously). During the follow-up phase, sub-cohorts formed aswomen switched to other COCs or stopped hormonal contraceptive use.These sub-cohorts included: COC_(Other) (i.e. users of COCs other thanNOMAC-E2 or COC_(LNG)), other hormonal contraceptives (OHC) (e.g. usersof progestin-only OCs, vaginal rings, intrauterine devices or implants)and Ex-users (i.e. women not using a hormonal contraceptive).

The NOMAC-E2 cohort had a higher mean age than the COC_(LNG) cohort andthe difference was statistically significant (NOMAC-E2: 31.0 years;COC_(LNG): 29.3 years). NOMAC-E2 users and COC_(LNG) users had a similarmean weight (NOMAC-E2: 63.3 kg; COC_(LNG): 63.1 kg) and mean BMI(NOMAC-E2: 23.2; COC_(LNG): 23.3). Gynaecological history and baselinerisk factors differed little between the cohorts.

Data from 144,901 women years (WY) of observation have been collected,including 48,846 WY from NOMAC-E2 users and 54,037 WY from COC_(LNG)users. The remaining observation time was contributed by the sub-cohortswhich formed during follow-up: COC_(Other) (8,300 WY), OHC (2,364 WY)and ex-users (31,354 WY).

Overall, there were 30 deaths: 10 due to accidents (3 in NOMAC-E2 users,3 in COC_(LNG) users, 1 in an OHC user and 3 in ex-users), 7 due tocancer (2 in NOMAC-E2 users and 5 in ex-users), 5 due to unknown causes(1 in a NOMAC-E2 user, 1 in a COC_(LNG) user and 3 in ex-users), 3 dueto infectious diseases (1 in a NOMAC-E2 user, 1 in a COC_(LNG) user and1 in an ex-user), 2 due to acute myocardial infarctions (AMIs) (1 in aCOC_(LNG) user and 1 in a COC_(Other) user), 1 due to a stroke (in anex-user), 1 due to cerebral edema (in a COC_(LNG) user) and 1 due toaccidental poisoning and exposure to noxious substances (in an ex-user).Blinded to the hormonal contraceptive exposure status, an independentSafety Monitoring and Advisory Council (SMAC) assessed that the deathswere unrelated to hormonal contraceptive use (19 deaths), a relationshipwas unlikely (4 deaths) or possible (3 deaths). Four other deaths (2COC_(LNG) users and 2 ex-users) were categorized as indeterminatebecause insufficient information was available to enable the SMAC toreasonably assess a relationship between death and hormonalcontraceptive use.

Overall, there were 34 VTEs in the main analysis of the primary outcome(DVT of the lower extremities and PE): 9 NOMAC-E2 (2.0 per 10,000 WY;95% CI, 0.9-3.7), 15 COC_(LNG) (3.0 per 10,000 WY; 95% CI, 1.7-5.0), 4COC_(Other) (5.2 per 10,000 WY; 95% CI, 1.4-13.4), 1 OHC (4.8 per 10,000WY; 95% CI, 0.1-26.8) and 5 ex-users (1.8 per 10,000 WY; 95% CI,0.6-4.1). The Cox proportional hazards a priori expert model (completecase analysis) resulted in a crude hazard ratio (HR_(crude)) forNOMAC-E2 versus COC_(LNG) of 0.65 (95% CI, 0.28-1.48). After adjustingfor age, BMI, family history of VTE and current duration of HC use, theadjusted hazard ratio (HR_(adj)) was 0.59 (95% CI, 0.25-1.35).

In total, 46 VTEs were included in the analysis of the secondary outcomeof all VTE (i.e. not restricted to DVT of the lower extremities and PE):12 NOMAC-E2 (2.5 per 10,000 WY; 95% CI, 1.3-4.3), 20 COC_(LNG) (3.7 per10,000 WY; 95% CI, 2.3-5.7), 5 COC_(Other) (6.0 per 10,000 WY; 95% CI,2.0-14.1), 1 OHC (4.2 per 10,000 WY; 95% CI 0.1-23.5) and 8 ex-users(2.6 per 10,000 WY; 95% CI, 1.1-5.0).

Overall, 35 of the 46 confirmed VTEs were considered idiopathic VTEs.The numbers and incidence rates for each (sub-)cohort were as follows:NOMAC-E2 10 VTEs (2.0 per 10,000 WY; 95% CI, 1.0 3.8), COC_(LNG) 15 VTEs(2.8 per 10,000 WY; 95% CI, 1.6-4.6), COC_(Other) 5 VTEs (6.0 per 10,000WY; 95% CI, 2.0-14.1), OHC 1 VTE (4.2 per 10,000 WY. 95% CI, 0.1-23.5)and ex-users 4 VTEs (1.3 per 10,000 WY; 95% CI, 0.35-3.3).

There were 16 confirmed ATEs: 4 NOMAC-E2 (0.8 per 10,000 WY; 95% CI,0.2-2.1), 7 COC_(LNG) (1.3 per 10,000 WY; 95% CI, 0.5-2.7), 1COC_(Other) (1.2 per 10,000 WY; 95% CI, 0.0-6.7) and 4 ex-users (1.3 per10,000 WY; 95% CI, 0.35-3.3).

Overall, there were 62 thrombolic events (VTE and ATE): 16 in NOMAC-E2users (3.3 per 10,000 WY; 95% CI, 1.9-5.3), 27 in COC_(LNG) users (5.0per 10,000 WY; 95% CI, 3.3-7.3), 6 in COC_(Other) users (7.2 per 10,000WY; 95% CI, 2.7-15.7), 1 in an OHC user (4.2 per 10,000 WY; 95% CI,0.1-23.5) and 12 in ex-users (3.8 per 10,000 WY; 95% CI, 2.0-6.7). A Coxregression analysis was performed to compare the risk in NOMAC-E2 usersversus COC_(LNG) users. The a priori expert model yielded an HR_(crude)of 0.68 (95% CI, 0.36-1.27) and, after adjusting for age, BMI, currentduration of HC use, family history of VTE and family history of ATE, anHR_(adj) of 0.64 (95% CI, 0.34-1.20).

There were 289 unintended pregnancies in hormonal contraceptive users:64 NOMAC-E2 (0.15 per 100 WY; 95% CI, 0.11-0.19), 200 COC_(LNG) (0.41per 100 WY; 95% CI, 0.35-0.47), 19 COC_(Other) (0.26 per 100 WY; 95% CI,0.16-0.40) and 6 OHC (0.28 per 100 WY; 95% CI, 0.10-0.61). Unintendedpregnancy was statistically significantly less likely in NOMAC-E2 userscompared to COC_(LNG) users (p<0.0001).

There were 261 cases of cholelithiasis (18.0 per 10,000 WY; 95% CI,15.9-20.3): 84 NOMAC-E2 (17.2 per 10,000 WY; 95% CI, 13.7-21.3), 92COC_(LNG) (17.0 per 10,000 WY; 95% CI, 13.7-20.9), 21 COCA her (25.3 per10,000 WY; 95% CI, 15.7-38.6), 8 OHC (33.8 per 10,000 WY; 95% CI,14.6-66.6) and 56 ex-users (17.9 per 10,000 WY; 95% CI, 13.5-23.2) Therewere 24 cases of inflammatory bowel disease: 4 NOMAC-E2 (0.8 per 10,000WY; 95% CI, 0.2-2.1), 13 COC_(LNG) (2.4 per 10,000 WY; 95% CI, 1.3-4.1),3 COC_(Other) (3.6 per 10,000 WY; 95% CI, 0.75-10.6) and 4 ex-users (1.3per 10,000 WY; 95% CI, 0.35-3.3).

Of the 191 cases of general hepatobiliary disorders, 65 were in NOMAC-E2users (13.3 per 10,000 WY; 95% CI, 10.3-17.0), 63 in COC_(LNG) users(11.7 per 10,000 WY; 95% CI, 9.0-14.9), 12 in COC_(Other) users (14.5per 10,000 WY; 95% CI, 7.5-25.2), 6 in OHC users (25.4 per 10,000 WY;95% CI, 9.3-55.2) and 45 in ex-users (14.4 per 10,000 WY; 95% CI,10.5-19.2).

There were 188 cases of new depression or worsening of an existingdepression: 46 cases in NOMAC-E2 users (9.4 per 10,000 WY; 95% CI,6.9-12.6), 80 in COC_(LNG) users (14.8 per 10,000 WY; 95% CI,11.7-18.4), 13 in COC_(Other) users (15.7 per 10,000 WY; 95% CI,8.3-26.8), 8 in OHC users (33.8 per 10,000 WY; 95% CI, 14.6-66.6) and 41in ex-users (13.1 per 10,000 WY; 95% CI, 9.4-17.7).

There was a trend for mean body weight to increase modestly betweenstudy entry and the follow-up time points for NOMAC-E2 and COC_(LNG)users.

In general, NOMAC-E2 users appeared to experience more of an improvementin their acne during follow-up (in comparison with baseline) thanCOC_(LNG) users.

Further details of this clinical study are provided below.

2. List of Abbreviations

-   -   AE Adverse Event    -   AMI Acute Myocardial Infarction    -   AT As Treated    -   ATE Arterial Thromboembolism BMI Body Mass Index    -   COC Combined Oral Contraceptive    -   COC_(LNG) Levonorgestrel-containing COC    -   COC_(LNGMono/20mcg) Monophasic levonorgestrel-containing COC        with 20 mcg ethinylestradiol    -   CO_(CLNGMono/30mcg) Monophasic levonorgestrel-containing COC        with 30 mcg ethinlyestradiol    -   COC_(LNGmulti) Multiphasic levonorgestrel-containing COC    -   COC_(Other) Combined oral contraceptive other than NOMAC-E2 or        COC_(LNG)    -   CT Computer Tomography    -   CVA Cerebrovascular Accidents    -   DVT Deep Venous Thrombosis    -   ECG Electrocardiogram    -   EE Ethinylestradiol    -   EURAS European Active Surveillance (study)    -   LNG Levonorgestrel    -   MRT Magnetic Resonance Tomography    -   MRI Magnetic Resonance Imaging    -   NOMAC-E2 Nomegestrol Acetate and Estradiol    -   HR Hazard ratio    -   HR_(adj) Hazard ratio (adjusted)    -   HR_(crude) Hazard ratio (crude)    -   OC Oral Contraceptive    -   OHC Other hormonal contraceptive (i.e., progestin-only method,        injections, implants, levonorgestrel-releasing intrauterine        devices, contraceptive patches)    -   PE Pulmonary Embolism    -   PIP Pediatric Investigation Plan    -   SAE Serious Adverse Event    -   VTE Venous Thromboembolism    -   WY Woman-years

3. Rationale and Background

NOMAC-E2 is a monophasic OC containing a fixed dose of nomegestrolacetate (2.5 mg) and 17β-estradiol (1.5 mg), which is taken for 24 daysfollowed by 4 days of placebo. Nomegestrol acetate has a strong affinityfor the progesterone receptor and has strong anti-gonadotropic activityand progesterone receptor-mediated anti-estrogenic activity, moderateanti-androgenic activity, and is devoid of estrogenic, androgenic,glucocorticoid or mineralocorticoid activity. The estrogen contained inNOMAC-E2 is 17β-estradiol, an estrogen identical to the endogenous human17β-estradiol.

Clinical experience with NOMAC-E2 and established COCs suggests thatserious clinical outcomes are rare when using NOMAC-E2 and other COCs(including COCs containing levonorgestrel (COC_(LNG))). One of the mostserious adverse events (AEs) associated with COC use is VTE. TheEuropean Active Surveillance Study (EURAS) comprehensively investigatedthe risk of VTE and other serious cardiovascular outcomes that might beassociated with OC use (see Dinger J C et al., Contraception. (2007) 75:344-354). However, similar comprehensive data from large, controlled,prospective studies with defined follow-up procedures of rare SAEs andlow loss to follow-up rates have not previously been made available forNOMAC-E2.

Data from randomized clinical trials has not revealed any serious healthconcerns for NOMAC-E2. However, the statistical power to detect rareadverse events has been limited in these earlier studies. Based ongeneral public concerns about the safety of COCs, the ProspectiveControlled Cohort Study on the Safety of a Monophasic Oral Contraceptivecontaining Nomegestrol Acetate (2.5 mg) and 17β-estradiol (1.5 mg),(PRO-E2) Study focused not only on VTE but also on ATE, depressivedisorders, cholelithiasis, general hepatobiliary disorders, inflammatorybowel disease, effects on fertility, pregnancy outcomes, weight changeand the effect on acne.

The PRO-E2 study was conducted as a required post-authorization safetystudy in accordance with Article 10a of the EU Regulation 726/2004. Theobjective of the PRO-E2 Study was to assess the cardiovascular and otherhealth risks associated with the use of NOMAC-E2 compared with the useof COC_(LNG) during standard clinical practice. The study included womenwho have been newly prescribed NOMAC-E2 or COC_(LNG) (either asfirst-ever users or as restarters with a COC intake break of at least 2months). During the follow-up phase, sub-cohorts formed as womenswitched to other COCs (forming a COC_(Other) sub-cohort), otherhormonal contraceptives such as progestin-only methods, injections,implants, levonorgestrel-releasing intrauterine devices andcontraceptive patches (forming an OHC sub-cohort), or stopped hormonalcontraceptive use (forming an Ex-user sub-cohort).

As specified in the study protocol dated 5 Feb. 2014, participatingcountries included Australia, Austria, France, Germany, Hungary, Italy,Poland, Russia and Spain. Subsequent to the approval of the StudyProtocol in April 2014, three additional countries (Mexico, Colombia andSweden) were included in the study (as reflected in the final version ofAmendment 1 of the Study Protocol, dated 20 Jun. 2019).

Patient recruitment began in August 2014 in Germany. Thereafter,recruitment began in Australia, Austria, Colombia, France, Hungary,Italy, Mexico, Poland, Russia, Spain and Sweden after country-specificrequirements were met.

4. Research Questions and Objectives

The primary objective of the study was to characterize and compare therisks of NOMAC-E2 use with COC_(LNG) use in a study population that isrepresentative of the actual users of the individual preparations. Thisincluded an estimate of the absolute risk of rare serious adverseoutcomes.

The main clinical outcomes of interest were VTE, specifically:

-   -   DVT of the lower extremities    -   PE

Secondary objectives of the study were to measure/describe for NOMAC-E2users and compare to users of COC_(LNG) during standard clinicalpractice:

-   -   All VTE, including thromboses of renal, mesenteric, portal and        retinal veins    -   ATE incidence rate. ATE includes acute myocardial infarction        (AMI) and cerebrovascular accidents (CVA)    -   Depressive disorders incidence rate (based on the assessment of        attending physicians who are specialized in psychiatry and the        Three Item Mental Health Inventory)    -   Cholelithiasis incidence rate    -   Inflammatory bowel disease incidence rate    -   Effect on fertility    -   Drug utilization pattern and baseline risk for primary and        secondary clinical outcomes—in particular cardiovascular        outcomes    -   Pregnancy outcomes

Additional secondary objectives were to measure/describe the followingfactors for NOMAC-E2 users and compare to users of COC_(LNG) duringstandard clinical practice:

-   -   Weight change    -   General hepatobiliary disorders    -   Effect on acne

5. Research Methods

Study Design

The study was a large, multinational, controlled, prospective, activesurveillance study that followed two cohorts. The cohorts consisted ofnew users (starters and restarters) of two different groups of hormonalcontraceptives: NOMAC-E2 and COC_(LNG). Starters were first-ever usersof any COC. Restarters were users who were restarting hormonalcontraceptive use with a COC (same COC as before or a new COC) after abreak of at least 2 months. This observational study providesstandardized, comprehensive, reliable information on these treatments ina routine clinical practice setting.

Study participants were recruited via an international network ofCOC-prescribing health care professionals (e.g. gynecologists, generalpractitioners, midwives). After study entry, study participants werefollowed for a period of 12 to 24 months for rare serious safetyoutcomes. Regular, active contact with the study participants providedthe necessary information on health-related events or changes in healthstatus. Additional follow-up procedures were used to validateself-reported events.

During the follow-up phase, direct contact with the study participantsallowed for almost all relevant clinical outcomes to be captured.However, laypersons often misclassified adverse events (e.g., pneumoniaas “pulmonary embolism” or migraine attacks as “stroke” even if modernimaging procedures do not provide any indication of the perceivedevent). This type of inaccuracy in patient reports required carefulvalidation of the reported events. This was accomplished by contactingthe relevant physicians (i.e. the treating physicians) and by reviewingsource documents. Under routine medical conditions, clinical outcomeswere not always confirmed by diagnostic procedures with highspecificity. Therefore, reported serious clinical outcomes wereclassified as “confirmed” or “not confirmed” by the physiciansoverseeing this study according to a predefined algorithm. At the end ofthe study, this classification was verified by blinded independentadjudication.

Setting

The PRO-E2 Study was divided into 2 phases: a patient-completed baselinesurvey, which involved an initial consultation at baseline with aparticipating physician during routine clinical practice; and afollow-up phase, which included two follow-up contacts with the patientduring the first year, and then a follow-up at 24 months after studyentry.

Subjects and Study Size, Including Dropouts

The overall recruitment target was 101,000 study participants (50,500NOMAC-E2 users and 50,500 COC_(LNG) users) recruited by participatingphysicians. This was planned to provide approximately 150,000 WY,assuming a drop-out rate of approximately 0.7% per month.

Subjects were considered for enrollment in the PRO-E2 Study after theparticipating physician and the woman had determined that NOMAC-E2 orCOC_(LNG) use was appropriate. There were no specific medicalinclusion/exclusion criteria and no age restrictions (to fulfill thepediatric investigation plan (PIP) requirement in the EU). However,women who 1) have been pregnant within 3 months before treatmentinitiation or 2) have a history of cancer/chemotherapy or an increasedgenetic risk for VTE at baseline were excluded from the analysis of VTE.

Once enrolled, a study participant could discontinue (and restart) useof hormonal contraception or could switch to another hormonalcontraceptive at any time. However, subjects continued to be followed upregardless of whether they remained on the prescribed contraceptive,provided that they did not withdraw their consent.

Variables

The following variables were recorded at baseline: ID number; date ofbirth; age at menarche; problems associated with menstrual period (e.g.irregular bleeding/spotting); hormonal contraceptive use (duration,brand name of most recent hormonal contraceptive, hormonal contraceptiveuse within the past two months); reason(s) for prescription; previouspregnancies; pregnancy within past three months; number of live births;number of miscarriages, stillbirths, abortions; family history of VTEand ATE; mood over the past four weeks; acne; impact of severe acne onself-esteem; medical history (including DVT, PE, myocardial infarction,stroke, thrombophilia or inherited increased risk of blood clots,depression requiring treatment, diseases of the liver, diseases of thegallbladder or biliary tract, inflammatory bowel disease, cancer,diabetes, high blood pressure, other severe diseases, operations);regular use of concomitant medication; height; weight; smoking statusand number of cigarettes smoked per day; level of education; date ofcompletion.

During follow-up, the following variables were recorded: ID number; newSAEs/AEs; hospitalization (planned/unplanned, reason, operationperformed); hormonal contraceptive use since last contact(stopped/switched/unchanged, reason for stopping/switching); concomitantmedication; pregnancy (occurrence, planned/unplanned, length of time tobecome pregnant, pregnant despite OC use, possible reasons forcontraceptive failure); delivery; serious health issues of the newborn;mood over the past four weeks; acne; impact of severe acne onself-esteem; smoking status and number of cigarettes smoked per day;weight; date of completion; change of personal contact details; name oftreating physician in case of SAE/AE.

Exposure

-   -   Cohort 1: NOMAC-E2    -   Cohort 2: Levonorgestrel-containing COCs: 1) monophasic        preparations containing 20-30 mcg of ethinylestradiol; 2)        multiphasic preparations containing up to 40 mcg of        ethinylestradiol

Outcome

The primary endpoint was VTE. Specific VTEs—DVT of the lower extremitiesand PE—were the primary outcomes of interest. Inferential statistics arebased on the VTE HR for NOMAC-E2 vs. COC_(LNG). This study provides datathat are sufficiently robust to eliminate a 1.5-fold risk in VTE forNOMAC-E2 compared to COC_(LNG).

The secondary endpoints also investigated are described above in theresearch questions and objectives section.

Covariates

In relation to VTE risk, the covariates include age, BMI, duration ofcurrent use and family history of VTE.

Data Sources and Measurement

Study participants documented on questionnaires their exposure tohormonal contraceptives and concomitant medications, the occurrence ofprimary and secondary outcomes and the existence of potentialconfounding factors and potential effect modifiers. If relevant,recruiting and attending physicians provided further information onadditional documentation sheets.

Follow-up assessments for each study participant were scheduled at 6months, 12 months and 24 months after study entry. Questionnaires wereprovided to the participating women. In some cases, events were reportedby the participant or by relatives, friends or attending physiciansbetween the regular follow-ups. All reports (independent of the sourceof information) were validated according to a standardized process

The follow-up questionnaires addressed the occurrence of adverse events(in particular, SAEs). If applicable, reasons for COC discontinuation ora switch to another hormonal contraceptive were requested.

Study Procedures

Under routine medical conditions, the diagnosis of an SAE is not alwaysconfirmed by a diagnostic method with high specificity. Therefore, SAEswere classified as “confirmed” or “not confirmed” according to thefollowing predefined algorithm:

-   -   Definite Event:    -   Confirmed by diagnostic measures with high specificity (e.g.        phlebography for DVT, spiral CT for PE, cerebral MRT for        cerebrovascular accidents, electrocardiogram (ECG) with typical        ST-segment elevation for acute myocardial infarction, histology        for gynecological cancer, two-sided blood pressure measurement        with diastolic blood pressure of more than 120 mmHg for        hypertensive crisis).    -   Probable Event:    -   Absence of confirmation by a diagnostic measure with high        specificity, but clinical diagnosis confirmed by a health        professional or supported by diagnostic tests with low        specificity (such as D-dimer for VTE or typical ECG/blood gas        tests for PE). These cases are usually characterized by a        subsequent specific therapy (such as fibrinolysis or long-term        anticoagulant therapy). However, if the attending physician        confirms that the diagnosis is correct, the event was classified        as a probable event even if specific treatment was not given.    -   Event not confirmed:        -   The diagnosis reported by the patient is excluded by            diagnostic procedures.        -   A different medical condition is diagnosed by the attending            physician.        -   The participant did not contact a health care professional            to clarify her symptoms and no diagnostic measures were            performed that could have clarified the diagnosis.

The exposure data reported by the patients was validated via theprescribing physicians. Definite and probable events were classified as‘confirmed events’.

For VTE, the definition of “definite”, “probable” and “not confirmed” isfurther specified:

-   -   Definite VTE: Confirmed by imaging procedure        -   DVT: phlebography, duplex sonography, or magnetic resonance            imaging (MRI).        -   PE: pulmonary angiography, ventilation-perfusion scan,            spiral computed tomography (CT), MRI, or transesophageal            echocardiography.    -   Probable VTE:    -   Absence of confirmation by an imaging test, but a clinical        diagnosis was confirmed by a health care professional or is        supported by a non-imaging test (such as ultrasound doppler,        plethysmography, D-dimer for VTE or typical ECG/blood gas tests        for PE). These cases are usually characterized by a subsequent        specific therapy (such as fibrinolysis or long-term        anticoagulant therapy). However, if the attending physician        confirmed that the diagnosis is correct, the event was        classified as a probable VTE, even if a specific treatment was        not given.    -   VTE not confirmed:        -   VTE excluded by a physician.        -   A different medical condition was diagnosed by the attending            physician.        -   Participant did not contact a health professional to clarify            her symptoms and no diagnostic measures were performed that            could have clarified the diagnosis.

For the final analysis this classification was verified by means of anindependent blinded adjudication process.

Study Size

The sample size considerations were based on the expected VTE incidencefor COC_(LNG). Sample size calculations were based on an incidence rateof 10 VTE per 10,000 WY¹ for COC_(LNG). ¹ ‘idiopathic’ PE and DVT of thelower extremities

The study was powered to test non-inferiority of NOMAC-E2 treatmentregarding VTE risk in comparison to COC_(LNG) use. The study wassufficiently powered to exclude a 1.5-fold VTE risk for NOMAC-E2 userscompared to COC_(LNG) users in the event that the true VTE risk amongNOMAC-E2 users is not higher than among COC_(LNG) users.

The sample size needed for the investigation of the VTE risk was alsosufficient for the evaluation of secondary outcomes (with the exceptionof ATE). Acute myocardial infarction and stroke are very rare in afemale population of reproductive age. The study was powered to excludea 2.5-fold risk of ATE in NOMAC-E2 users compared to COC_(LNG) users.This was sufficient to screen for safety signals and substantialeffects.

Statistical Methods

Main Summary Measures

Incidence rates, crude HRs and adjusted HRs were calculated.

Main Statistical Methods

The study used a non-inferiority design to investigate the VTE risk ofNOMAC-E2. The a priori assumption was that use of NOMAC-E2 is notassociated with an increased risk of VTE compared to COC_(LNG) (i.e. astatistical comparison of NOMAC-E2 and COC_(LNG) is not expected to showa difference).

6. Results

Participants

A total of 103,463 women were enrolled in the study after having beenrecruited by 2,413 physicians in Australia, Austria, Colombia, France,Germany, Hungary, Italy, Mexico, Poland, Russia, Spain and Sweden. Theresults of the analyses presented herein are based on 102,330 women.

Descriptive Data

Of the 91,313 women in the AT population, a total of 44,559 wereNOMAC-E2 users and 46,754 were COC_(LNG) users (48.8% and 51.2% of thestudy population, respectively). Of the 46,754 COC_(LNG) users, 20,181(22.1% of the total study population) were users of a monophasicpreparation containing 20 mcg of EE, 17,469 (19.1% of the total studypopulation) were users of a monophasic preparation containing 30 mcg ofEE and 9,104 (10% of the total study population) were users ofmultiphasic preparations.

At study entry, the mean age of NOMAC-E2 users was higher (31.0 years)than COC_(LNG) users (29.3 years) and this difference was statisticallysignificant (p<0.0001). There were no substantial differences inrelation to mean weight (NOMAC-E2: 63.3 kg; COC_(LNG): 63.1 kg) or meanBMI (NOMAC-E2: 23.2; COC_(LNG): 23.3). The distribution of cohorts byage category is displayed in FIG. 1 . Almost 33% of NOMAC-E2 users and27% of COC_(LNG) users were aged 35 or older.

As noted above, starters and restarters of COCs are included in thestudy population. Starters comprised 62.2% of NOMAC-E2 users and 64.4%of COC_(LNG) users. Restarters comprised 37.8% and 35.6% of NOMAC-E2 andCOC_(LNG) users, respectively.

The distribution of cohorts by age category is displayed in FIG. 1 .Both user cohorts had a similar weight (NOMAC-E2: 63.3 kg; COC_(LNG):63.0 kg) and a mean BMI indicative of a healthy weight (NOMAC-E2: 23.2;COC_(LNG): 23.3).

Characteristics associated with gynaecological history were largelysimilar between the cohorts at study entry. This included the mean ageat menarche (12.8 years for each cohort), the mean age at first deliveryamong parous women (NOMAC-E2: 24.3 years; COC_(LNG): 23.7 years), themedian number of live births (if ever pregnant) (1.0 in each cohort) andthe median number of miscarriages/stillbirths/abortions (if everpregnant) (1.0 in each cohort). A greater proportion of NOMAC-E2 usersreported ever having been pregnant (NOMAC-E2: 57.0%; COC_(LNG): 54.9%).

In this real world observational study, women were asked for thereason(s) for their contraceptive prescription. With regard to themotivating factors behind COC use, 54.9% of NOMAC-E2 users reportedseeking a COC prescription for contraceptive reasons only compared to57.1% of COC_(LNG) users. The proportions of women who reportedcontraceptive as well as non-contraceptive reasons were 33.9% and 33.1%for NOMAC-E2 and COC_(LNG) users, respectively. Meanwhile, 9.5% ofNOMAC-E2 users and 8.6% of COC_(LNG) users reported using COCsexclusively for non-contraceptive reasons (such as cycle control, acne,painful and/or prolonged/heavy bleeding).

The non-contraceptive reasons specified by study participants aredisplayed in Table 1. Sometimes women reported more than onenon-contraceptive reason.

TABLE 1 Non-contraceptive reasons for COC prescription reported bypatients at study entry, by cohort NOMAC-E2 COC_(LNG) Total (N = 50,187)(N = 52,143) (N = 102,330) Patient-reported reason n % n % n % Cycleregulation 9,360 42.1 10,263 46.7 19,623 44.4 Painful menstrual bleeding8,624 38.8 8,753 39.9 17,377 39.3 Heavy and/or prolonged menstrual 5,94326.8 5,105 23.2 11,048 25.0 bleeding Acne 2,178 9.8 1,875 8.5 4,053 9.2Ovarian cysts 1,784 8.0 1,838 8.4 3,622 8.2 Polycystic ovary syndrome(PCOS) 1,328 6.0 1,334 6.1 2,662 6.0 Premenstrual syndrome (PMS) 1,2935.8 1,047 4.8 2,340 5.3 Endometriosis 1,335 6.0 863 3.9 2,198 5.0Bleeding on demand 551 2.5 617 2.8 1,168 2.6 Premenstrual dysphoricdisorder (PMDD) 217 1.0 143 0.7 360 0.8 Other reasons 1,572 7.1 1,3386.1 2,910 6.6 Note: Women could report multiple reasons.

At study entry, women were also asked about (i) history of treateddepression; and (ii) history of acne. There were no significantdifferences between the cohorts. Women were also asked about theirpersonal history of disease and regular medication use.

Outcome Data

Fatal Outcomes

A total of 30 study participants died during the study. Among theNOMAC-E2 users, 7 deaths were reported: 3 due to accidents, 2 due tocancer (one woman died of end stage lymphoma with metastasis to theliver and the other of vulvar cancer with widespread metastasis), 1 as aresult of a systemic herpes infection and 1 due to an unknown cause.

Blinded to the hormonal contraceptive exposure status, the SMAC assessedthat in 19 of the deaths there was no relationship to hormonalcontraceptive use. One case involving a NOMAC-E2 user with a history ofheart disease who died due to an unknown cause was assessed by the SMACas having a possible relationship to hormonal contraceptive use becausethe cause of death was unknown. One case involving an Ex-user who diedof an unknown cause was assessed as unlikely to be related to hormonalcontraceptive use. In relation to another case involving an Ex-user whodied of an unknown cause, the SMAC assessed the relationship withhormonal contraceptive use as ‘indeterminate’ because insufficientinformation is known to enable an assessment of a causal relationship.

SAEs

There were a total of 3,388 SAEs. An SAE is defined in this study as anadverse event that results in death, a life-threatening experience,inpatient hospitalization, persistent or significantdisability/incapacity, or requires medical/surgical intervention toprevent one of these outcomes.

The incidence of SAE was significantly lower in NOMAC-E2 users than inCOC_(LNG) users. Of 3,388 SAEs, 983 occurred in NOMAC-E2 users, 1,225 inCOC_(LNG) users, 224 in COC_(Other) users, 40 in OHC users and 916 inex-users. The corresponding incidence rates per 10,000 WY (and 95%confidence intervals) for each user cohort were as follows: 201.2(189.0-214.1) for NOMAC-E2, 226.7 (214.3-239.6) for COC_(LNG), 269.9(236.1-307.0) for COC_(Other), 169.2 (121.2-229.7) for OHC and 292.1(273.8-311.4) for ex-users. FIG. 2 graphically displays the incidencerates and 95% confidence intervals.

Malignant Neoplasm

A comparison of the user (sub-)cohorts showed no relevant difference: 41NOMAC-E2 (8.4 per 10,000 WY; 95% CI, 6.0-11.4), 43 COC_(LNG) (8.0 per10,000 WY; 95% CI, 5.8-10.7), 5 COC_(Other) (6.0 per 10,000 WY; 95% CI,2.0-14.1), 1 OHC (4.2 per 10,000 WY; 95% CI, 0.1-23.5) and 40 ex-users(12.8 per 10,000 WY; 95% CI, 9.1-17.4). The most frequent cases involvedbreast cancer: 11 NOMAC-E2 (2.3 per 10,000 WY; 95% CI, 1.1-4.0), 13COC_(LNG) (2.4 per 10,000 WY; 95% CI, 1.3-4.1), 4 COC_(Other) (4.8 per10,000 WY; 95% CI, 1.3-12.3), 1 OHC (4.2 per 10,000 WY; 95% CI,0.1-23.5) and 19 ex-users (6.1 per 10,000 WY; 95% CI, 3.6-9.5).

Main Results

During the reporting period, data from a total of 144,901 WY ofobservation were collected. In addition to the cohorts at study entry(NOMAC-E2 and COC_(LNG)), a number of additional cohorts developedduring the follow-up phase as women switched to other forms ofcontraception or discontinued contraceptive use altogether. Table 2displays the number of WY within each of the user cohorts.

TABLE 2 Number of WY of observation within each (sub)-cohort Percentageof User (sub-)cohort Woman years observation time NOMAC-E2 48,846 33.7COC_(LNG) 54,037 37.3 COC_(Other) 8,300  5.7 Other hormonalcontraceptive 2,364  1.6 (OHC)* Ex-user (no hormonal 31,354 21.6contraceptive use) Total 144,901 100**  *Progestin-only OC, vaginalring, injection, intrauterine device, contraceptive patch or implant.**Discrepancy due to rounding.

Primary Outcome of Interest

DVT of the Lower Extremities and PE

Overall, there have been 38 confirmed VTE comprising the primary outcomeof interest (DVT of the lower extremities and PE): 10 in NOMAC-E2 users(2.0 per 10,000 WY; 95% CI, 1.0-3.8), 17 in COC_(LNG) users (3.1 per10,000 WY; 95% CI, 1.8-5.0), 4 in COC_(Other) users (4.8 per 10,000 WY;95% CI, 1.3-12.3), 1 in an OHC user (4.2 per 10,000 WY; 95% CI,0.1-23.5) and 6 in ex-users (1.9 per 10,000 WY; 95% CI, 0.7-4.2) (FIG. 3). Five women (2 COC_(LNG) users and 3 COC_(Other) users) experiencedboth a DVT of a lower extremity and a PE. The point estimates and 95%confidence intervals per user (sub)-cohort are in Table 3.

TABLE 3 DVT of the lower extremities and PE: Numbers, incidence ratesper 10,000 WY and 95% confidence intervals per (sub)-cohort NOMAC-E2COC_(LNG) COC_(Other) OHC Ex-user Total (48,846 WY) (54,037 WY) (8,300WY) (2,364 WY) (31,354 WY) (144,901 WY) Incidence** Incidence**Incidence** Incidence** Incidence** Incidence** Category n (95% Cl) n(95% Cl) n (95% Cl) n (95% Cl) n (95% Cl) n (95% Cl) DVT of lower 10 2.017 3.1 4 4.8 1 4.2 6 1.9 38 2.6 extremities and PE (1.0-3.8) (1.8-5.0)(1.3-12.3) (0.1-23.5) (0.7-4.2) (1.9-3.6) Thereof: DVT  7 1.4 12 2.2 44.8 0 0.0 2 0.6 25 1.7 (0.6-3.0) (1.1-3.9) (1.3-12.3) (0.0-15.6)(0.1-2.3) (1.1-2.5) PE  3 08  7 1.3 3 3.6 1 4.2 4 1.3 18 1.2 (0.1-1.8)(0.5-2.7) (0.75-10.6) (0.1-23.5) (0.35-3.3) (0.7-2.0) *Pregnant within 3months of treatment initiation, history of cancer/chemotherapy or anincreased genetic risk of VTE (e.g. Factor V Leiden, Protein S or Cdeficiency). **Incidence rate per 10,000 WY Note: Five women (2COC_(LNG) users and 3 COC_(Other) users) experienced both a DVT and aPE.

DVT of the Lower Extremities and PE after Excluding Women withPre-Defined Risk Factors at Study Entry

Risk estimates of VTE may be influenced by women who are pregnant within3 months of treatment initiation, have a history of cancer/chemotherapyor an increased genetic risk of VTE (e.g. Factor V Leiden, Protein S orC deficiency). Therefore, an analysis was planned which would excludeall women who reported these pre-defined risk factors at study entry.This resulted in the exclusion of 4 VTE being excluded from theanalysis: 2 COC_(LNG) users and 1 ex-user who had been pregnant within 3months of study entry and 1 NOMAC-E2 user who had a history ofcancer/chemotherapy. Therefore, this analysis was based on 34 confirmedVTE comprising the primary outcome of interest (DVT of the lowerextremities and PE): 9 in NOMAC-E2 users (2.0 per 10,000 WY; 95% CI,0.9-3.7), 15 in COC_(LNG) users (3.0 per 10,000 WY; 95% CI, 1.7-5.0), 4in COC_(Other) users (5.2 per 10,000 WY; 95% CI, 1.4-13.4), 1 in an OHCuser (4.8 per 10,000 WY; 95% CI, 0.1-26.8) and 5 in ex-users (1.8 per10,000 WY; 95% CI, 0.6-4.1) (FIG. 4 ). The number of (primary outcome)VTE, point estimates and 95% confidence intervals for the (sub)-cohortsare presented in Table 4.

TABLE 4 DVT of the lower extremities and PE among women without knownpre- defined risk factors at baseline: Numbers, incidence rates per10,000 WY and 95% confidence intervals per (sub)-cohort NOMAC-E2COC_(LNG) COC_(Other) OHC Ex-user Total (45,780 WY) (49,729 WY) (7,620WY) (2,073 WY) (28,372 WY) (133,544 WY) Incidence** Incidence**Incidence** Incidence** Incidence** Incidence** Category n (95% Cl) n(95% Cl) n (95% Cl) n (95% Cl) n (95% Cl) n (95% Cl) DVT of lower 6 2.015 3.0 4 5.2 1 4.8 5 1.8 34 2.5 extremities and PE (0.9-3.7) (1.7-5.0)(1.4-13.4) (0.1-26.8) (0.6-4.1) (1.8-3.6) Thereof: DVT 6 1.3 11 2.2 45.2 0 0.0 1 0.35 22 1.6 (0.5-2.9) (1.1-4.0) (1.4-13.4) (0.0-17.8)(0.01-2.0) (1.8-2.5) PE 3 0.7  6 1.2 3 3.9 1 4.8 4 1.4 17 1.3 (0.1-1.9)(0.4-2.6) (0.8-11.5) (0.1-26.8) (0.4-3.6) (0.7-2.0) *Women who werepregnant within 3 months of treatment initiation, had a history ofcancer/chemotherapy or an increased genetic risk of VTE (e.g. Factor VLeiden, Protein S or C deficiency). **Incidence rate per 10,000 WY Note:Five woman (2 COC_(LNG) users and 3 COC_(Other) users) experienced botha DVT and a PE.

NOMAC-E2 use does not appear to be associated with a higher risk of VTEcompared with the use of other COCs. The HR_(crude) for NOMAC-E2 vs.COC_(LNG) of 0.65 with a 95% confidence interval of 0.28-1.48. Afteradjusting for age, BMI, family history of VTE and current duration of HCuse, HR_(adj) was 0.59 (95% CI, 0.25-1.35).

Multiple imputation analysis resulted in an HR_(crude) for NOMAC-E2 vs.COC_(LNG) of 0.65 (95% CI, 0.28-1.48). After adjusting for age, BMI(multiple imputation), family history of VTE and current duration of HCuse, the HR_(adj) was 0.59 (95% CI, 0.25-1.35).

DVT of the Lower Extremities and PE Limited to Women Using COCs forContraceptive Purposes Only

An analysis was performed which was limited to women who reported thattheir motivation for their prescription at study entry was forcontraceptive reasons only.

There were a total of 17 VTEs (2.4 per 10,000 WY; 95% CI, 1.4-3.9) inwomen who reported that their motivation for using the COC was forcontraceptive reasons only: 4 VTEs in NOMAC-E2 users (1.6 per 10,000 WY;95% CI, 0.45-4.2), 10 VTEs in COC_(LNG) users (3.6 per 10,000 WY; 95%CI, 1.7-6.7), 1 VTE in a COC_(Other) user (2.8 per 10,000 WY; 95% CI,0.1-15.7) and 2 VTEs in ex-users (1.5 per 10,000 WY; 95% CI, 0.2-5.5)(FIG. 5 ). Table 5 displays the number of VTE, point estimates and 95%confidence intervals for the (sub)-cohorts.

TABLE 5 DVT of the lower extremities and PE among women who reported atstudy entry that their motivation for NOMAC-E2 or COC_(LNG) use was forcontraceptive reasons only: Numbers, incidence rates per 10,000 WY and95% confidence intervals per (sub)-cohort NOMAC-E2 COC_(LNG) COC_(Other)OHC Ex-user Total (24,354 WY) (27,443 WY) (3,554 WY) (1,043 WY) (13,020WY) (69,414 WY) Incidence*** Incidence*** Incidence*** Incidence***Incidence*** Incidence*** Category n (95% Cl) n (95% Cl) n (95% Cl) n(95% Cl) n (95% Cl) n (95% Cl) DVT of lower 4 1.6 3.6 1 2.8 0 0.0 2 1.517 2.4 extremities and PE (0.45-4.2) (1.7-6.7) (0.1-15.7) (0.0-35.3)(0.2-5.5) (1.4-3.9) Thereof: DVT 2 0.8 2.2 1 2.8 0 0.0 1 0.8 10 1.4(0.1-3.0) (0.8-4.8) (0.1-15.7) (0.0-35.3) (0.0-4.3) (0.7-2.6) PE 2 0.82.2 1 2.8 0 0.0 1 0.8 10 1.4 (0.1-3.0) (0.8-4.8) (0.1-15.7) (0.0-35.3)(0.0-4.3) (0.7-2.6) *Pregnant within 3 months of treatment initiation,history of cancer/chemotherapy or an increased genetic risk of VTE (e.g.Factor V Leiden, Protein S or C deficiency). **Reason(s) forcontraceptive use were captured only at study entry and were notnecessarily relevant at the time of the event. ***Incidence rate per10,000 WY Note: Threee women (2 COC_(LNG) users and 1 COC_(Other) users)experienced both a DVT and a PE.

DVT of the Lower Extremities and PE by Geographical Region

Excluding Russia

The low overall incidence rate of DVT of the lower extremities and PEobserved in this study (2.5 per 10,000 WY; 95% CI, 1.8-3.6) can mainlybe explained by the particularly low rate of VTE observed in the Russianstudy participants who comprise a large proportion (39.5%) of the PRO-E2study population.

If Russia is excluded from the VTE analysis, the resulting incidencerates are 3.3 per 10,000 WY (95% CI, 1.4-6.5) for NOMAC-E2 and 4.7 per10,000 WY (95% CI, 2.6-7.8) for COC_(LNG) (FIG. 6 ).

Excluding Australia, Colombia and Mexico

Analysis of the primary endpoint in which data from Australia, Colombiaand Mexico were excluded, resulted in the calculation of risk estimatesbased on 33 VTE: 9 in NOMAC-E2 users (2.0 per 10,000 WY; 95% CI,0.9-3.9), 14 in COC_(LNG) users (3.0 per 10,000 WY; 95 CI, 1.7-5.1), 4in COC_(Other) users (5.4 per 10,000 WY; 95% CI, 1.5-13.7) and 5 inEx-users (1.8 per 10,000 WY; 95% CI, 0.6-4.3).

DVT of the Lower Extremities and PE by User Status (Starters VsRestarters)

A stratified analysis of VTE per user status (starters, restarters) didnot indicate a higher VTE risk for NOMAC-E2. There were 16 VTEs (DVT ofthe lower extremities and PE) among starters: 5 in NOMAC-E2 users (1.7per 10,000 WY; 95% CI, 0.6-4.0), 6 in COC_(LNG) users (1.9 per 10,000WY; 95% CI, 0.7-4.1), 3 in COC_(Other) users (7.4 per 10,000 WY; 95% CI,1.5-21.7) and 2 in ex-users (1.3 per 10,000 WY; 95% CI, 0.15-4.6). Therewere 18 VTEs (DVT of the lower extremities and PE) among restarters: 4in NOMAC-E2 users (2.4 per 10,000 WY; 95% CI, 0.6-6.1), 9 in COC_(LNG)users (5.0 per 10,000 WY; 95% CI, 2.3-9.5), 1 in a COC_(Other) user (2.8per 10,000 WY; 95% CI, 0.1-15.5), 1 in an OHC user (9.4 per 10,000 WY;95% CI, 0.2-52.4) and 3 in ex-users (2.4 per 10,000 WY; 95% CI,0.5-6.9).

DVT of the Lower Extremities and PE by Type of Preparation (MonophasicVs Multiphasic)

The risk of VTE in NOMAC-E2 users was compared with the risk in users ofmonophasic COC_(LNG) preparations containing 20 mcg EE(COC_(LNGMono/20mcg)), COC_(LNG) preparations containing 30 mcg EE(COC_(LNGMono/30mcg)) and in users of multiphasic COC_(LNG) preparations(COC_(LNGMulti)). There were 9 VTEs in NOMAC-E2 users (2.0 per 10,000WY; 95% CI 0.9-3.7), 11 in COC_(LNGMono/20mcg) users (4.9 per 10,000 WY;95% CI, 2.4-8.7), 1 in a COC_(LNGMono/30mcg) user (0.6 per 10,000 WY;95% CI, 0.0-3.2) and 3 in COC_(LNGMulti) users (3.2 per 10,000 WY; 95%CI, 0.7-9.3).

Hazard ratios (crude and after adjusting for age, BMI, family history ofVTE and current duration of use) were calculated. A comparison ofNOMAC-E2 to monophasic COC_(LNG) preparations with 20 mcg EE resulted inan HR_(crude) of 0.4 (95% CI, 0.1-1.1) and the HR_(adj) was 0.3 (95% CI,0.1-1.0). The HR_(crude) for NOMAC-E2 vs. COC_(LNGMono/30mcg) was 2.5(95% CI, 0.3-20.6) and the HR_(adj) was 2.6 (95% CI, 0.3-21.4). TheHR_(crude) for NOMAC-E2 vs. COC_(LNGmulti) was 0.5 (95% CI, 0.1-1.8) andthe HR_(adj) was 0.4 (95% CI, 0.1-1.6).

Secondary Outcomes of Interest

All VTE

A total of 46 VTEs were confirmed. In addition to the 38 VTEs comprisinga DVT of the lower extremities or PE (the primary outcome of interest)referred to in Table 33, there were 8 additional DVTs: 2 in NOMAC-E2users (1 in the arm and 1 in the portal vein), 3 in COC_(LNG) users (2in the arm and 1 in the sinus vein), 1 in a COC_(Other) user (in thearm) and 2 in ex-users (both in the subclavian vein). The numbers andincidence rates for each (sub-)cohort were as follows: NOMAC-E2 12 VTEs(2.5 per 10,000 WY; 95% CI, 1.3-4.3), COC_(LNG) 20 VTEs (3.7 per 10,000WY; 95% CI, 2.3-5.7), COC_(Other) 5 VTEs (6.0 per 10,000 WY; 95% CI,2.0-14.1), OHC 1 VTE (4.2 per 10,000 WY; 95% CI, 0.1-23.5) and ex-users8 VTEs (2.6 per 10,000 WY; 95% CI, 1.1-5.0) (FIG. 7 ).

TABLE 6 displays the number of VTE, point estimates and 95% confidenceintervals for the (sub)-cohorts. Category NOMAC-E2 COC_(LNG) COC_(Other)OHC Ex-user Total (48,846 WY) (54,037 WY) (8,300 WY) (2,364 WY) (31,354WY) (144,901 WY) Incidence* Incidence* Incidence* Incidence* Incidence*Incidence* n (95% Cl) n (95% Cl) n (95% Cl) n (95% Cl) n (95% Cl) n (95%Cl) All VTE 12 2.5 20 3.7 5 6.0 1 4.2 8 2.6 46 3.2 (1.3-4.3) (2.3-5.7)(2.0-14.1) (0.1-23.5) (1.1-5.0) (2.3-4.2) Thereof: DVT of lower 10 2.017 3.1 4 4.6 1 4.2 6 1.9 38 2.6 extremities and PE (1.0-3.6) (1.8-6.0)(1.3-12.3) (0.1-23.5) (0.7-4.2) (1.9-3.6) All other DVT  2 0.4  3 0.56 11.2 0 0.0 2 0.6  8 0.55 (0.05-1.5) (0.1-1.6) (0.0-6.7) (0.0-15.6)(0.1-2.3) (0.2-1.1) *Incidence rate per 10,000 WY

Idiopathic VTE

Overall, 35 of the 46 confirmed VTEs were considered idiopathic VTEs.The numbers and incidence rates for each (sub-)cohort are as follows:NOMAC-E2 10 VTEs (2.0 per 10,000 WY; 95% CI, 1.0-3.8), COC_(LNG) 15 VTEs(2.8 per 10,000 WY; 95% CI, 1.6-4.6), COC_(Other) 5 VTEs (6.0 per 10,000WY; 95% CI, 2.0-14.1), OHC 1 VTE (4.2 per 10,000 WY. 95% CI, 0.1-23.5)and ex-users 4 VTEs (1.3 per 10,000 WY; 95% CI, 0.35-3.3)Summary of VTEresults

A summary of the results of the numerous analyses which were conductedto evaluate the risk of VTE in NOMAC-E2 users compared with COC_(LNG)users is displayed in Table 7.

TABLE 7 Summary of results of VTE analyses: Numbers, events, incidencerates per 10,000 WY and 95% confidence intervals in NOMAC-E2 users andCOC_(LNG) users NOMAC-E2 COC_(LNG) Incidence* Incidence* Category

(95% CI)

(95% CI) Primary outcome (DVT lower extremities and PE) Main analysis(excluding women with pre-defined risk 9 2.0 15 3.0 factors** at studyentry) (0.9-3.7) (1.7-5.0) Adolescents only 0 0.0 2 5.9 (0.0-21.3)(0.7-21.4) Excluding Russia 8 3.3 15 4.7 (1.4-6.5) (2.6-7.8) ExcludingAustralia and Latin America 9 2.0 14 3.0 (0.9-3.9) (1.7-5.1) IncludingMexico 9 1.9 15 3.0 (0.9-3.7) (1.7-5.0) Starters only 5 1.7 6 1.9(0.56-4.0) (0.7-4.1) Restarters only 4 2.4 9 5.0 (0.6-6.1) (2.3-9.5)Including ICD-10 code

80.3*** 10 2.2 16 3.2 (1.0-4.0) (1.8-5.2) Allocation of one VTE to COC

 rather than NOMAC-E2 8 1.7 15 3.0 (0.75-3.4) (1.7-5.0) COC used forcontraceptive reasons only 4 1.6 10 3.6 (0.45-4.2) (1.7-6.7) MonophasicCOC_(LNG) with 20 mcg EE 9 2.0 11 4.9 (0.9-3.7) (2.4-8.7) MonophasicCOC_(LNG) with 30 mcg EE 9 2.0 1 0.6 (0.9-3.7) (0.01-3.2) MultiphasicCOC_(LNG) 9 2.0 3 3.2 (0.9-3.7) (0.66-9.3) Including women withpre-defined risk factors** at study 10 2.0 17 3.1 entry) (0.98-3.8)(1.8-5.0) Secondary outcome (All VTE) 12 2.5 20 3.7 (1.3-4.3) (2.3-5.7)Confirmed and possible VTE 14 2.9 21 3.9 (1.6-4.8) (2.4-5.9) Confirmed,possible and potential VTE 20 4.1 28 5.2 (2.5-5.3) (3.4-7.5) Secondaryoutcome (Idiopathic VTE) 10 2.0 15 2.8 (0.98-3.8) (1.6-4.6) *Incidencerate per 10,000 WY **Pregnant within 3 months of treatment initiation,history of cancer/chemotherapy or an increased genetic risk for VTE(e.g. Factor V Leiden, Protein S or C deficiency) at baseline.***Phlebitis and thrombophlebitis lower extremities, unspecified.

indicates data missing or illegible when filed

Other Secondary Outcomes

There were 289 unintended pregnancies in hormonal contraceptive users:64 NOMAC-E2 (0.15 per 100 WY; 95% CI, 0.11-0.19), 200 COC_(LNG) (0.41per 100 WY; 95% CI, 0.35-0.47), 19 COC_(Other) (0.26 per 100 WY; 95% CI,0.16-0.40) and 6 OHC (0.28 per 100 WY; 95% CI, 0.10-0.61). Unintendedpregnancy was statistically significantly less likely in NOMAC-E2 userscompared to COC_(LNG) users (p<0.0001).

A total of 16 ATEs were confirmed: 4 ATEs (2 ischemic strokes, 1 TIA and1 myocardial infarction) in NOMAC-E2 users (0.8 per 10,000 WY; 95% CI,0.2-2.1), 7 ATEs (4 ischemic strokes and 3 AMI) in COC_(LNG) users (1.3per 10,000 WY; 95% CI, 0.5-2.7), 1 ATE (an AMI) in a COC_(Other) user(1.2 per 10,000 WY; 95% CI, 0.0-6.7) and 4 ATEs (3 ischemic strokes and1 AMI) in ex-users (1.3 per 10,000 WY; 95% CI, 0.35-3.3).

There were 24 cases of inflammatory bowel disease. The numbers andincidences per (sub-) cohort were as follows: 4 in NOMAC-E2 users (0.8per 10,000 WY; 95% CI, 0.2-2.1), 13 in COC_(LNG) users (2.4 per 10,000WY; 95% CI, 1.3-4.1), 3 in COC_(Other) users (3.6 per 10,000 WY; 95% CI,0.75-10.6) and 4 in ex-users (1.3 per 10,000 WY; 95% CI, 0.35-3.3).

There were 261 cases of cholelithiasis (18.0 per 10,000 WY; 95% CI,15.9-20.3): 84 NOMAC-E2 (17.2 per 10,000 WY; 95% CI, 13.7-21.3), 92COC_(LNG) (17.0 per 10,000 WY; 95% CI, 13.7-20.9), 21 COC_(Other) (25.3per 10,000 WY; 95% CI, 15.7-38.6), 8 OHC (33.8 per 10,000 WY; 95% CI,14.6-66.6) and 56 ex-users (17.9 per 10,000 WY; 95% CI, 13.5-23.2) Therewere 24 cases of inflammatory bowel disease: 4 NOMAC-E2 (0.8 per 10,000WY; 95% CI, 0.2-2.1), 13 COC_(LNG) (2.4 per 10,000 WY; 95% CI, 1.3-4.1),3 COC_(Other) (3.6 per 10,000 WY; 95% CI, 0.75-10.6) and 4 ex-users (1.3per 10,000 WY; 95% CI, 0.35-3.3).

Of the 191 cases of general hepatobiliary disorders, 65 were in NOMAC-E2users (13.3 per 10,000 WY; 95% CI, 10.3-17.0), 63 in COC_(LNG) users(11.7 per 10,000 WY; 95% CI, 9.0-14.9), 12 in COC_(Other) users (14.5per 10,000 WY; 95% CI, 7.5-25.2), 6 in OHC users (25.4 per 10,000 WY;95% CI, 9.3-55.2) and 45 in ex-users (14.4 per 10,000 WY; 95% CI,10.5-19.2).

There were 188 cases of new depression or worsening of an existingdepression: 46 cases in NOMAC-E2 users (9.4 per 10,000 WY; 95% CI,6.9-12.6), 80 in COC_(LNG) users (14.8 per 10,000 WY; 95% CI,11.7-18.4), 13 in COC_(Other) users (15.7 per 10,000 WY; 95% CI,8.3-26.8), 8 in OHC users (33.8 per 10,000 WY; 95% CI, 14.6-66.6) and 41in ex-users (13.1 per 10,000 WY; 95% CI, 9.4-17.7).

Mean body weight increased modestly between each follow-up time point(6, 12 and 24 months after study entry) in comparison with baseline forboth NOMAC-E2 and COC_(LNG) users. In general, NOMAC-E2 users appearedto experience more of an improvement in their acne during follow-up (incomparison with baseline) than COC_(LNG) users.

Review of Power Calculations

The sample size calculations specified in the study protocol were basedon an incidence of 10 VTE per 10,000 WY for COC_(LNG). Sample sizecalculations for a non-inferiority test of two exponential survivalcurves showed that an expected number of 150 VTE cases would besufficient to reach this goal. These calculations were based on thefollowing assumptions: 1) one-sided α of 0.05; 2) power (1-p) of 0.80and 3) non-inferiority limit on a HR of 1.5. At an incidence rate of10/10,000 WY a total of 150 VTE could be expected within 150,000 WY.

The results presented herein indicate that at this point in time, therisk of VTE is not equal among NOMAC-E2 users and COC_(LNG) users. Inrelation to the primary outcome of interest

(DVT of the lower extremities and PE) among women without pre-definedrisk factors at study entry, the HR_(crude) for NOMAC-E2 vs. COC_(LNG)is 0.6 with a 95% confidence interval of 0.2 to 1.5. After adjusting forage, BMI, family history of VTE and current duration of use, theHR_(adj) for NOMAC-E2 vs. COC_(LNG) remained 0.6 (0.2-1.5).

Interpretation

These results demonstrate that NOMAC-E2 users are not at higher risk ofVTE, ATE, death, SAE, cholelithiasis, inflammatory bowel disease,general hepatobiliary disorders, depressive disorders, mood changes,weight changes or acne changes compared to COC_(LNG) users. They alsodemonstrate the NOMAC-E2 users are at a reduced risk of unintendedpregnancy compared to COC_(LNG) users.

Generalisation

The study was designed to reflect routine clinical use of COCs. Studyparticipants were recruited by COC-prescribing healthcare professionals(e.g. gynecologists, general practitioners, midwives) and all new usersof COCs could participate in the study. Participation was not limited bymedical inclusion and exclusion criteria. Therefore, the ability togeneralize the results of this study is high.

7. Summary

Baseline Characteristics

-   -   NOMAC-E2 users had a higher mean age at study entry compared to        COC_(LNG) users. Other baseline characteristics (including        cardiovascular risk factors) were similar between the user        cohorts. The similarities between the cohorts would indicate        that confounding should be minimal.

Primary Outcome of Interest

-   -   The risk of DVT of the lower extremities and PE (VTE) was lower        in the NOMAC-E2 cohort (2.0 per 10,000 WY; 95% CI, 0.9-3.7),        compared to the COC_(LNG) cohort (3.0 per 10,000 WY; 95% CI,        1.7-5.0).    -   The HR_(crude) for NOMAC-E2 vs. COC_(LNG) was 0.65 with a 95%        confidence interval of 0.28 to 1.48. After adjusting for age,        BMI, family history of VTE and current duration of use, HR_(adj)        remained 0.6 (95% CI, 0.25-1.35).    -   COC_(LNG) are considered to be one of the CHCs associated with        the lowest risk of VTE in patients and consequently are used as        first line CHCs. This study reports for the first time that        NOMAC-E2 is associated with a lower risk of VTE compared to        COC_(LNG). Therefore, this study supports the use of NOMAC-E2 as        a first line CHC.

Secondary Outcomes of Interest

-   -   The risk of all VTE was lower in the NOMAC-E2 cohort (2.5 per        10,000 WY; 95% CI, 1.3-4.3) compared to the COC_(LNG) cohort        (3.7 per 10,000 WY; 95% CI, 2.3-5.7).    -   The risk of idiopathic VTE was lower in NOMAC-E2 users (2.0 per        10,000 WY; 95% CI, 1.0 3.8) compared to COC_(LNG) users (2.8 per        10,000 WY; 95% CI, 1.6-4.6).    -   There were no statistically significant differences between        NOMAC-E2 users and COC_(LNG) users in relation to the risk of        ATE, cholelithiasis, inflammatory bowel disease, general        hepatobiliary disorders, depressive disorders, mood changes,        weight or acne.    -   The risk of unintended pregnancy was statistically significantly        lower in the NOMAC-E2 cohort (0.15 per 100 WY; 95% CI,        0.11-0.19) than the COC_(LNG) cohort (0.41 per 100 WY; 95% CI,        0.35-0.47) (p<0.0001) In general, NOMAC-E2 users appeared to        experience more of an improvement in their acne during follow-up        (in comparison with baseline) than COC_(LNG) users.

1. A composition for use in reducing the risk of venous thromboembolismassociated with the use of combined oral contraceptives, wherein thecomposition comprises nomegestrol acetate and estradiol or an esterthereof.
 2. The composition for use according to claim 1, wherein therisk of deep vein thrombosis is reduced.
 3. The composition for useaccording to claim 1 or claim 2, wherein the risk of pulmonary embolismis reduced.
 4. The composition for use according to any one of thepreceding claims, wherein the risk of venous thromboembolism is reducedrelative to a combined oral contraceptive containing levonorgestrel; andoptionally ethinylestradiol.
 5. The composition for use according to anyone of the preceding claims, wherein the risk of venous thromboembolismis reduced by at least 40%.
 6. The composition for use according to anyone of the preceding claims, wherein the Hazard Ratio is 0.5-0.6.
 7. Thecomposition for use according to any one of the preceding claims,wherein the composition is administered to a woman or women ofchild-bearing age as a means of contraception.
 8. The composition foruse according to any one of the preceding claims, wherein thecomposition is administered to a woman or women for a non-contraceptiveuse.
 9. The composition for use according to claim 8 wherein thenon-contraceptive use is selected from (i) the treatment of a conditionselected from painful menstrual bleeding, heavy and/or prolongedmenstrual bleeding, acne, ovarian cysts, polycystic ovary syndrome,premenstrual syndrome, endometriosis, or premenstrual dysphoricdisorder; and/or (ii) menstrual cycle regulation.
 10. The compositionfor use according to any one of the preceding claims, wherein thecomposition is administered to a woman or women identified as atincreased risk of venous thromboembolism.
 11. The composition for useaccording to any one of the preceding claims, wherein the composition isadministered to a woman or women 35 years of age or above.
 12. Thecomposition for use according to any one of the preceding claims,wherein the composition is administered to a woman or women having abody mass index in excess of 30 kg/m² and/or a woman or women withdiabetes.
 13. The composition for use according to any one of thepreceding claims, wherein the composition is administered to a woman orwomen having a condition selected from: cancer; systemic lupuserythematosus; haemolytic uraemic syndrome; chronic inflammatory boweldisease, optionally Crohn's disease or ulcerative colitis; and sicklecell disease.
 14. The composition for use according to any one of thepreceding claims, wherein the composition is administered to a woman orwomen who has/have not received prior combined oral contraceptivetreatment.
 15. The composition for use according to any one of claims1-13, wherein the composition is administered to a woman or women whohave previously received combined oral contraceptive treatment.
 16. Thecomposition for use according to any one of the preceding claims,wherein the nomegestrol acetate and estradiol or ester thereof arepresent in the composition in a weight ratio of approximately 1.67 to 1.17. The composition for use according to any one of the precedingclaims, wherein the nomegestrol acetate is present in an amount rangingfrom about 1.5 mg to about 3.75 mg.
 18. The composition for useaccording to any one of the preceding claims, wherein the estradiol orester thereof is present in an amount ranging from about 0.5 mg to about3 mg.
 19. The composition for use according to any one of the precedingclaims, wherein the estradiol is 17β-estradiol; optionally wherein the17β-estradiol is in hemihydrate form.
 20. The composition for useaccording to any one of the preceding claims, wherein the nomegestrolacetate is present in an amount of about 2.5 mg and the estradiol ispresent in an amount of about 1.5 mg.
 21. The composition for useaccording to any one of the preceding claims, wherein the composition isadministered daily for a period of 21 to 28 days; optionally for aperiod of 24 consecutive days.
 22. The composition for use according toany one of the preceding claims, wherein the composition is in the formof plain or film-coated tablets, sugar-coated tablets, soft gelatincapsules, wafer capsules, pills, cachets or powders.
 23. The compositionfor use according to any one of the preceding claims, wherein thecomposition further comprises at least one excipient selected from:lactose monohydrate; microcrystalline cellulose (E460); crospovidone(E1201); talc (E553b); magnesium stearate (E572); and colloidalanhydrous silica; or any combination thereof.
 24. The composition foruse according to any one of the preceding claims wherein the compositioncomprises: 2.5 mg nomegestrol acetate; 1.5 mg 17β-estradiol; 57.7 mglactose monohydrate; 14 mg microcrystalline cellulose; 2.4 mgcrospovidone; 0.7 mg talc; 0.7 mg magnesium stearate, and 0.44 mgcolloidal anhydrous silica.
 25. The composition for use according to anyone of the preceding claims, wherein the composition is provided as apharmaceutical kit comprising a plurality of dosage units and optionallyat least one placebo.
 26. Use of a composition comprising nomegestrolacetate and estradiol or an ester thereof as a contraceptive; whereinthe risk of venous thromboembolism associated with the use of combinedoral contraceptives is reduced.
 27. A method of contraception, whereinthe method comprises administering to a woman a composition comprisingnomegestrol acetate and estradiol or an ester thereof, wherein the riskof venous thromboembolism associated with the use of combined oralcontraceptives is reduced in the woman administered the composition. 28.A composition for use in a method of treating a condition selected from:painful menstrual bleeding; heavy and/or prolonged menstrual bleeding;acne; ovarian cysts; polycystic ovary syndrome; premenstrual syndrome;endometriosis; and premenstrual dysphoric disorder, wherein thecomposition comprises nomegestrol acetate and estradiol or an esterthereof; and wherein the risk of venous thromboembolism associated withthe use of combined oral contraceptives is reduced.
 29. A method ofreducing the risk of venous thromboembolism associated with the use ofcombined oral contraceptives, wherein the method comprises administeringto a woman a composition comprising nomegestrol acetate and estradiol oran ester thereof.